Coronaviruses — drug discovery and therapeutic options
Identifieur interne : 000557 ( Pmc/Corpus ); précédent : 000556; suivant : 000558Coronaviruses — drug discovery and therapeutic options
Auteurs : Alimuddin Zumla ; Jasper F. W. Chan ; Esam I. Azhar ; David S. C. Hui ; Kwok-Yung YuenSource :
- Nature Reviews. Drug Discovery [ 1474-1776 ] ; 2016.
Abstract
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are examples of emerging zoonotic coronavirus infections capable of person-to-person transmission that result in large-scale epidemics with substantial effects on patient health and socioeconomic factors. Unlike patients with mild illnesses that are caused by other human-pathogenic coronaviruses, patients with SARS or MERS coronavirus infections may develop severe acute respiratory disease with multi-organ failure. The case–fatality rates of SARS and MERS are approximately 10% and 35%, respectively. Both SARS and MERS pose major clinical management challenges because there is no specific antiviral treatment that has been proven to be effective in randomized clinical trials for either infection. Substantial efforts are underway to discover new therapeutic agents for coronavirus infections. Virus-based therapies include monoclonal antibodies and antiviral peptides that target the viral spike glycoprotein, viral enzyme inhibitors, viral nucleic acid synthesis inhibitors and inhibitors of other viral structural and accessory proteins. Host-based therapies include agents that potentiate the interferon response or affect either host signalling pathways involved in viral replication or host factors utilized by coronaviruses for viral replication. The major challenges in the clinical development of novel anti-coronavirus drugs include the limited number of suitable animal models for the evaluation of potential treatments for SARS and MERS, the current absence of new SARS cases, the limited number of MERS cases — which are also predominantly geographically confined to the Middle East — as well as the lack of industrial incentives to develop antivirals for mild infections caused by other, less pathogenic coronaviruses. The continuing threat of MERS-CoV to global health 3 years after its discovery presents a golden opportunity to tackle current obstacles in the development of new anti-coronavirus drugs. A well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, should be formed to carry out clinical trials using anti-coronavirus drugs that have already been shown to be safe and effective
The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1038/nrd.2015.37
PubMed: 26868298
PubMed Central: 7097181
Links to Exploration step
PMC:7097181Le document en format XML
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Coronaviruses — drug discovery and therapeutic options</title>
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307 Euston Road, NW1 3AD London UK</nlm:aff>
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<series><title level="j">Nature Reviews. Drug Discovery</title>
<idno type="ISSN">1474-1776</idno>
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<front><div type="abstract" xml:lang="en"><title>Key Points</title>
<p id="Par6"><list list-type="bullet"><list-item><p id="Par7">Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are examples of emerging zoonotic coronavirus infections capable of person-to-person transmission that result in large-scale epidemics with substantial effects on patient health and socioeconomic factors. Unlike patients with mild illnesses that are caused by other human-pathogenic coronaviruses, patients with SARS or MERS coronavirus infections may develop severe acute respiratory disease with multi-organ failure. The case–fatality rates of SARS and MERS are approximately 10% and 35%, respectively.</p>
</list-item>
<list-item><p id="Par8">Both SARS and MERS pose major clinical management challenges because there is no specific antiviral treatment that has been proven to be effective in randomized clinical trials for either infection. Substantial efforts are underway to discover new therapeutic agents for coronavirus infections.</p>
</list-item>
<list-item><p id="Par9">Virus-based therapies include monoclonal antibodies and antiviral peptides that target the viral spike glycoprotein, viral enzyme inhibitors, viral nucleic acid synthesis inhibitors and inhibitors of other viral structural and accessory proteins.</p>
</list-item>
<list-item><p id="Par10">Host-based therapies include agents that potentiate the interferon response or affect either host signalling pathways involved in viral replication or host factors utilized by coronaviruses for viral replication.</p>
</list-item>
<list-item><p id="Par11">The major challenges in the clinical development of novel anti-coronavirus drugs include the limited number of suitable animal models for the evaluation of potential treatments for SARS and MERS, the current absence of new SARS cases, the limited number of MERS cases — which are also predominantly geographically confined to the Middle East — as well as the lack of industrial incentives to develop antivirals for mild infections caused by other, less pathogenic coronaviruses.</p>
</list-item>
<list-item><p id="Par12">The continuing threat of MERS-CoV to global health 3 years after its discovery presents a golden opportunity to tackle current obstacles in the development of new anti-coronavirus drugs. A well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, should be formed to carry out clinical trials using anti-coronavirus drugs that have already been shown to be safe and effective <italic>in vitro</italic>
and/or in animal models, particularly lopinavir–ritonavir, interferon beta-1b and monoclonal antibodies and antiviral peptides targeting the viral spike glycoprotein.</p>
</list-item>
</list>
</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Rev Drug Discov</journal-id>
<journal-id journal-id-type="iso-abbrev">Nat Rev Drug Discov</journal-id>
<journal-title-group><journal-title>Nature Reviews. Drug Discovery</journal-title>
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<issn pub-type="ppub">1474-1776</issn>
<issn pub-type="epub">1474-1784</issn>
<publisher><publisher-name>Nature Publishing Group UK</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26868298</article-id>
<article-id pub-id-type="pmc">7097181</article-id>
<article-id pub-id-type="publisher-id">BFnrd201537</article-id>
<article-id pub-id-type="doi">10.1038/nrd.2015.37</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Coronaviruses — drug discovery and therapeutic options</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Zumla</surname>
<given-names>Alimuddin</given-names>
</name>
<xref ref-type="aff" rid="Aff1">1</xref>
<bio><p id="Par1">Alimuddin Zumla is professor of infectious diseases and international health in the division of Infection and Immunity at University College London (UCL), UK, a consultant infectious diseases physician at UCL Hospitals NHS Foundation Trust, UK, and a founding director of the University of Zambia–UCL Medical School (<ext-link ext-link-type="uri" xlink:href="http://www.unza-uclms.org/">UNZA–UCLMS</ext-link>
) Research and Training Programme. He has published over 400 PubMed articles and 21 textbooks. His research has defined the epidemiology and clinical features and improved diagnostics, drug treatment and management protocols of lethal respiratory infectious diseases in Sub-Saharan Africa, the Middle East, the United Kingdom and Europe.</p>
</bio>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Chan</surname>
<given-names>Jasper F. W.</given-names>
</name>
<xref ref-type="aff" rid="Aff2">2</xref>
<bio><p id="Par2">Jasper F. W. Chan is a clinical assistant professor at the State Key Laboratory of Emerging Infectious Diseases, the Carol Yu Centre for Infection, the Research Centre of Infection and Immunology and the Department of Microbiology at the University of Hong Kong (HKU) and is a specialist in clinical microbiology and infection at Queen Mary Hospital in Hong Kong, China, and HKU-Shenzhen Hospital in Shenzhen, China. He received his M.B.B.S. from HKU in 2005 and completed postgraduate specialist training to become a fellow of the Royal College of Physicians (Edinburgh, UK), the Royal College of Pathologists (UK), the Hong Kong College of Pathologists and the Hong Kong Academy of Medicine. He has published over 120 peer-reviewed articles on emerging infectious diseases, particularly those caused by novel coronaviruses.</p>
</bio>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Azhar</surname>
<given-names>Esam I.</given-names>
</name>
<xref ref-type="aff" rid="Aff3">3</xref>
<bio><p id="Par3">Esam I. Azhar is Head of the Special Infectious Agents Unit, and Associate Professor of Medical Virology at the King Fahd Medical Research Centre, Kind Abdul Aziz University, Jeddah, Saudi Arabia. He obtained his M.Sc. and Ph.D. from the University of Sheffield, UK, and is a Fellow of the Royal College of Physicians (Edinburgh, UK). He has published over 70 publications and has made seminal contributions to research on Alkhurma viral haemorrhagic fever, dengue haemorrhagic fever virus, Rift Valley fever virus and Middle East respiratory syndrome coronavirus.</p>
</bio>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Hui</surname>
<given-names>David S. C.</given-names>
</name>
<xref ref-type="aff" rid="Aff4">4</xref>
<bio><p id="Par4">David S. C. Hui is the Stanley Ho Professor of Respiratory Medicine and the Director of the Stanley Ho Centre for Emerging Infectious Diseases at the Chinese University of Hong Kong (CUHK). He graduated from the University of New South Wales, Australia, in 1985, and then trained in Respiratory and Sleep Medicine in Sydney, Australia. He has published well over 240 peer-reviewed journal articles and 23 book chapters since joining the CUHK in 1998. His research interests include the clinical management of severe acute respiratory infections, the safety of respiratory therapy and hospital infection control in the post-SARS (severe acute respiratory syndrome) era.</p>
</bio>
</contrib>
<contrib contrib-type="author" corresp="yes" equal-contrib="yes"><name><surname>Yuen</surname>
<given-names>Kwok-Yung</given-names>
</name>
<address><email>kyyuen@hku.hk</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
<bio><p id="Par5">Kwok-Yung Yuen is the Henry Fok Professor and Chair of Infectious Diseases at The University of Hong Kong (HKU). He also serves as the director of the clinical diagnostic microbiology services at Queen Mary Hospital in Hong Kong, China, and HKU-Shenzhen Hospital in Shenzhen, China, as the co-director of the State Key Laboratory of Emerging Infectious Diseases of China in Hong Kong and as the founding co-director of the HKU-Pasteur Research Centre in Hong Kong. He is an elected Academician of the Chinese Academy of Engineering (Basic Medicine and Health), a founding member of the Academy of Sciences of Hong Kong, and a Fellow of the Royal College of Physicians (London and Edinburgh, UK; as well as Ireland), Royal College of Surgeons (Glasgow, UK) and Royal College of Pathologists (UK). His has published over 800 peer-reviewed articles in the areas of emerging infections and microbial discovery. He and his team have discovered and characterized over 60 novel human and animal viruses, including human coronavirus HKU1 and the bat and human severe acute respiratory syndrome (SARS) coronaviruses.</p>
</bio>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.83440.3b</institution-id>
<institution-id institution-id-type="ISNI">0000000121901201</institution-id>
<institution>Division of Infection and Immunity,</institution>
<institution>University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust,</institution>
</institution-wrap>
307 Euston Road, NW1 3AD London UK</aff>
<aff id="Aff2"><label>2</label>
Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Research Centre of Infection and Immunology, University Pathology Building, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region of the People's Republic of China</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="GRID">grid.412125.1</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 0619 1117</institution-id>
<institution>and Medical Laboratory Technology Department,</institution>
<institution>Special Infectious Agents Unit, King Fahd Medical Research Centre, Faculty of Applied Medical Sciences, King Abdulaziz University,</institution>
</institution-wrap>
P.O. Box 128442, 21362 Jeddah Kingdom of Saudi Arabia</aff>
<aff id="Aff4"><label>4</label>
Division of Respiratory Medicine and Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Prince of Wales Hospital, 30–32 Ngan Shing Street, Shatin, New Territories Hong Kong Special Administrative Region of the People's Republic of China</aff>
</contrib-group>
<pub-date pub-type="epub"><day>12</day>
<month>2</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="ppub"><year>2016</year>
</pub-date>
<volume>15</volume>
<issue>5</issue>
<fpage>327</fpage>
<lpage>347</lpage>
<permissions><copyright-statement>© Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2016</copyright-statement>
<license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p>
</license>
</permissions>
<abstract id="Abs1" abstract-type="KeyPoints"><title>Key Points</title>
<p id="Par6"><list list-type="bullet"><list-item><p id="Par7">Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are examples of emerging zoonotic coronavirus infections capable of person-to-person transmission that result in large-scale epidemics with substantial effects on patient health and socioeconomic factors. Unlike patients with mild illnesses that are caused by other human-pathogenic coronaviruses, patients with SARS or MERS coronavirus infections may develop severe acute respiratory disease with multi-organ failure. The case–fatality rates of SARS and MERS are approximately 10% and 35%, respectively.</p>
</list-item>
<list-item><p id="Par8">Both SARS and MERS pose major clinical management challenges because there is no specific antiviral treatment that has been proven to be effective in randomized clinical trials for either infection. Substantial efforts are underway to discover new therapeutic agents for coronavirus infections.</p>
</list-item>
<list-item><p id="Par9">Virus-based therapies include monoclonal antibodies and antiviral peptides that target the viral spike glycoprotein, viral enzyme inhibitors, viral nucleic acid synthesis inhibitors and inhibitors of other viral structural and accessory proteins.</p>
</list-item>
<list-item><p id="Par10">Host-based therapies include agents that potentiate the interferon response or affect either host signalling pathways involved in viral replication or host factors utilized by coronaviruses for viral replication.</p>
</list-item>
<list-item><p id="Par11">The major challenges in the clinical development of novel anti-coronavirus drugs include the limited number of suitable animal models for the evaluation of potential treatments for SARS and MERS, the current absence of new SARS cases, the limited number of MERS cases — which are also predominantly geographically confined to the Middle East — as well as the lack of industrial incentives to develop antivirals for mild infections caused by other, less pathogenic coronaviruses.</p>
</list-item>
<list-item><p id="Par12">The continuing threat of MERS-CoV to global health 3 years after its discovery presents a golden opportunity to tackle current obstacles in the development of new anti-coronavirus drugs. A well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, should be formed to carry out clinical trials using anti-coronavirus drugs that have already been shown to be safe and effective <italic>in vitro</italic>
and/or in animal models, particularly lopinavir–ritonavir, interferon beta-1b and monoclonal antibodies and antiviral peptides targeting the viral spike glycoprotein.</p>
</list-item>
</list>
</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<abstract id="Abs2" abstract-type="web-summary"><p id="Par13">Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development.</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<abstract id="Abs3"><p id="Par14">In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, respectively, have received global attention over the past 12 years owing to their ability to cause community and health-care-associated outbreaks of severe infections in human populations. These two viruses pose major challenges to clinical management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiology, virology, clinical features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.</p>
<sec><title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/nrd.2015.37) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group kwd-group-type="npg-subject"><title>Subject terms</title>
<kwd>SARS virus</kwd>
<kwd>Vaccines</kwd>
<kwd>Drug discovery</kwd>
<kwd>Infectious diseases</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© Springer Nature Limited 2016</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
<body><sec id="Sec1"><title>Main</title>
<p id="Par15">Coronaviruses (CoVs; subfamily <italic>Coronavirinae</italic>
, family <italic>Coronaviridae</italic>
, order <italic>Nidovirales</italic>
) are a group of highly diverse, enveloped, positive-sense, single-stranded RNA viruses that cause respiratory, enteric, hepatic and neurological diseases of varying severity in a broad range of animal species, including humans<sup><xref ref-type="bibr" rid="CR1">1</xref>
,<xref ref-type="bibr" rid="CR2">2</xref>
,<xref ref-type="bibr" rid="CR3">3</xref>
</sup>
. CoVs are subdivided into four genera: <italic>Alphacoronavirus</italic>
, <italic>Betacoronavirus</italic>
(βCoV), <italic>Gammacoronavirus</italic>
and <italic>Deltacoronavirus</italic>
<sup><xref ref-type="bibr" rid="CR2">2</xref>
,<xref ref-type="bibr" rid="CR3">3</xref>
,<xref ref-type="bibr" rid="CR4">4</xref>
,<xref ref-type="bibr" rid="CR5">5</xref>
,<xref ref-type="bibr" rid="CR6">6</xref>
,<xref ref-type="bibr" rid="CR7">7</xref>
</sup>
. Over the past 12 years, two novel βCoVs, severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV), have emerged, and these viruses can cause severe human diseases<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. The lack of effective drug treatment and associated high morbidity and mortality rates of these two CoVs as well as their potential to cause epidemics highlight the need for novel drug discovery for the treatment of CoV infections.</p>
</sec>
<sec id="Sec2"><title>Epidemiology of SARS and MERS</title>
<p id="Par16"><bold><italic>SARS.</italic>
</bold>
SARS-CoV emerged first in southern China and rapidly spread around the globe in 2002–2003 (Refs <xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR11">11</xref>
). In November 2002, an unusual epidemic of atypical pneumonia with a high rate of nosocomial transmission to health-care workers occurred in Foshan, Guangdong, China<sup><xref ref-type="bibr" rid="CR12">12</xref>
,<xref ref-type="bibr" rid="CR13">13</xref>
</sup>
. In March 2003, a novel CoV was confirmed to be the causative agent for SARS, and was thus named SARS-CoV<sup><xref ref-type="bibr" rid="CR14">14</xref>
,<xref ref-type="bibr" rid="CR15">15</xref>
,<xref ref-type="bibr" rid="CR16">16</xref>
,<xref ref-type="bibr" rid="CR17">17</xref>
</sup>
. A 64-year-old nephrologist who travelled from southern China to Hong Kong on 21 February 2003 became the index case of subsequent large community and health-care-associated outbreaks of SARS in Hong Kong and other regions<sup><xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR11">11</xref>
,<xref ref-type="bibr" rid="CR18">18</xref>
,<xref ref-type="bibr" rid="CR19">19</xref>
,<xref ref-type="bibr" rid="CR20">20</xref>
,<xref ref-type="bibr" rid="CR21">21</xref>
</sup>
. The high infectivity of SARS was highlighted by the super-spreading event at a major teaching hospital in Hong Kong in which 138 people, including many previously healthy health-care workers, were infected within 2 weeks of exposure to an index patient who was being managed in a general medical ward for community-acquired pneumonia<sup><xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR22">22</xref>
</sup>
. Through international air travel, SARS-CoV was spread to 29 countries and regions with a total of 8,098 cases and 774 fatalities (9.6% of cases) by the end of the epidemic in July 2003 (Ref. <xref ref-type="bibr" rid="CR23">23</xref>
) (see <xref rid="MOESM12" ref-type="media">Supplementary information S1 (figure, parts a,b)</xref>
).</p>
<p id="Par17">A retrospective serological survey suggested that cross-species transmission of SARS-CoV or its variants from animal species to humans might have occurred frequently in the wet market, where high seroprevalence was detected among asymptomatic animal handlers<sup><xref ref-type="bibr" rid="CR24">24</xref>
</sup>
. A close variant of SARS-CoV was isolated in palm civets in Dongmen market, Shenzhen, China, in 2003 (Ref. <xref ref-type="bibr" rid="CR25">25</xref>
). During the small-scale SARS outbreaks in late 2003 and early 2004, three of the four patients had direct or indirect contact with palm civets<sup><xref ref-type="bibr" rid="CR26">26</xref>
,<xref ref-type="bibr" rid="CR27">27</xref>
</sup>
. However, viral genetic sequence analysis demonstrated that the SARS-CoV-like virus had not been circulating among masked palm civets in markets for a long time, and a serological study showed that only caged market civets and not wild civets were infected with the SARS-CoV-like virus<sup><xref ref-type="bibr" rid="CR28">28</xref>
</sup>
. CoVs that are highly similar to SARS-CoV have been isolated from Chinese horseshoe bats since 2005 (Refs <xref ref-type="bibr" rid="CR29">29</xref>
,<xref ref-type="bibr" rid="CR30">30</xref>
,<xref ref-type="bibr" rid="CR31">31</xref>
,<xref ref-type="bibr" rid="CR32">32</xref>
). These SARS-like CoVs from bats share 88–95% sequence homology with human or civet CoV isolates, which suggests that bats were probably the natural reservoir of a close ancestor of SARS-CoV<sup><xref ref-type="bibr" rid="CR4">4</xref>
,<xref ref-type="bibr" rid="CR33">33</xref>
,<xref ref-type="bibr" rid="CR34">34</xref>
</sup>
.</p>
<p id="Par18"><bold><italic>MERS.</italic>
</bold>
The isolation of a novel βCoV from a patient in Jeddah, Saudi Arabia, who died of severe pneumonia and multi-organ failure in June 2012, was first reported in September 2012 (Ref. <xref ref-type="bibr" rid="CR35">35</xref>
). Initially named 'human coronavirus Erasmus Medical Center', the virus was later renamed MERS-CoV by international consensus, and the disease was called Middle East respiratory syndrome (MERS)<sup><xref ref-type="bibr" rid="CR36">36</xref>
</sup>
. Retrospective analysis of a cluster of nosocomial cases in April 2012 in Jordan confirmed that MERS-CoV was also responsible for that outbreak<sup><xref ref-type="bibr" rid="CR37">37</xref>
</sup>
. Over the past 3 years, MERS-CoV has continued to spread within and beyond the Middle East, and there are ongoing reports of sporadic cases and community and health-care-associated clusters of infected individuals in the Middle East, especially in Saudi Arabia and the United Arab Emirates<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR38">38</xref>
</sup>
. Travel-related cases and clusters have also been increasingly reported on other continents<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. As of 9 October 2015, 1,593 laboratory-confirmed cases of MERS, including 568 deaths, have been reported to the World Health Organization<sup><xref ref-type="bibr" rid="CR39">39</xref>
</sup>
(see <xref rid="MOESM12" ref-type="media">Supplementary information S1 (figure, parts c,d)</xref>
).</p>
<p id="Par19">MERS-CoV is considered primarily to be a <xref rid="Glos1" ref-type="list">zoonotic virus</xref>
that has the capability of non-sustained person-to-person spread<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. Serological and virological studies have shown that camels and bats are the most likely animal reservoirs of MERS-CoV<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR40">40</xref>
,<xref ref-type="bibr" rid="CR41">41</xref>
,<xref ref-type="bibr" rid="CR42">42</xref>
,<xref ref-type="bibr" rid="CR43">43</xref>
,<xref ref-type="bibr" rid="CR44">44</xref>
,<xref ref-type="bibr" rid="CR45">45</xref>
,<xref ref-type="bibr" rid="CR46">46</xref>
,<xref ref-type="bibr" rid="CR47">47</xref>
</sup>
. Although not all primary cases of MERS were individuals who had direct contact with camels, such exposure is considered to be an important factor for the spread of MERS-CoV, as evidenced by the substantially increased seroprevalence of anti-MERS-CoV antibodies among individuals with occupational exposure to camels, such as camel shepherds and slaughterhouse workers, relative to the general population in Saudi Arabia<sup><xref ref-type="bibr" rid="CR48">48</xref>
,<xref ref-type="bibr" rid="CR49">49</xref>
</sup>
. Person-to-person transmission of MERS-CoV has occurred in health-care facilities and family clusters<sup><xref ref-type="bibr" rid="CR50">50</xref>
,<xref ref-type="bibr" rid="CR51">51</xref>
,<xref ref-type="bibr" rid="CR52">52</xref>
,<xref ref-type="bibr" rid="CR53">53</xref>
</sup>
. The recent, large health-care-associated outbreaks in Jeddah and South Korea have been attributed to poor compliance with infection control measures<sup><xref ref-type="bibr" rid="CR54">54</xref>
,<xref ref-type="bibr" rid="CR55">55</xref>
</sup>
. Further studies are needed to fully understand the exact mode of transmission and other potential sources of MERS-CoV for optimization of treatment and prevention strategies for MERS<sup><xref ref-type="bibr" rid="CR56">56</xref>
,<xref ref-type="bibr" rid="CR57">57</xref>
</sup>
.</p>
<p id="Par20"><bold><italic>Clinical features of SARS and MERS.</italic>
</bold>
Patients with SARS or MERS present with various clinical features, ranging from asymptomatic or mild respiratory illness to fulminant severe acute respiratory disease with extrapulmonary manifestations<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. Both diseases have predominantly respiratory manifestations, but extrapulmonary features may occur in severe cases<sup><xref ref-type="bibr" rid="CR56">56</xref>
</sup>
(see <xref rid="MOESM12" ref-type="media">Supplementary information S2 (table)</xref>
). Notably, early treatment is especially important for patients with severe MERS because this disease progresses to respiratory distress, renal failure and death much more rapidly than SARS does. The three- to four-fold higher case-fatality rate of MERS relative to SARS may be related to the higher median age and prevalence of comorbidities in patients with MERS as well as the different pathogenesis of the two diseases<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR58">58</xref>
,<xref ref-type="bibr" rid="CR59">59</xref>
,<xref ref-type="bibr" rid="CR60">60</xref>
,<xref ref-type="bibr" rid="CR61">61</xref>
</sup>
. Comorbidities associated with severe MERS include obesity, diabetes mellitus, systemic immunocompromising conditions and chronic cardiac and pulmonary diseases<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR60">60</xref>
,<xref ref-type="bibr" rid="CR62">62</xref>
,<xref ref-type="bibr" rid="CR63">63</xref>
</sup>
. Although the rate of secondary transmission among household contacts of index MERS patients (which is approximately 4%) and the estimated pandemic potential of MERS-CoV are lower than those of SARS-CoV, the rapidly progressive clinical course and high fatality of MERS continues to pose a major threat to at-risk populations<sup><xref ref-type="bibr" rid="CR64">64</xref>
,<xref ref-type="bibr" rid="CR65">65</xref>
,<xref ref-type="bibr" rid="CR66">66</xref>
,<xref ref-type="bibr" rid="CR67">67</xref>
,<xref ref-type="bibr" rid="CR68">68</xref>
,<xref ref-type="bibr" rid="CR69">69</xref>
,<xref ref-type="bibr" rid="CR70">70</xref>
,<xref ref-type="bibr" rid="CR71">71</xref>
</sup>
(see <xref rid="MOESM12" ref-type="media">Supplementary information S2 (table)</xref>
).</p>
<p id="Par21"><bold><italic>Current management strategies for SARS and MERS.</italic>
</bold>
Supportive care — including organ support and prevention of complications, especially acute respiratory distress syndrome, organ failure and secondary nosocomial infections — remains the most important management strategy for SARS and MERS, as there is currently no specific antiviral treatment that has been proven to be effective in randomized controlled trials<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR56">56</xref>
,<xref ref-type="bibr" rid="CR72">72</xref>
,<xref ref-type="bibr" rid="CR73">73</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR75">75</xref>
</sup>
. Numerous compounds have been found to inhibit the entry and/or replication of SARS-CoV and MERS-CoV in cell culture or in animal models, but activity <italic>in vitro</italic>
and even in animal experiments does not necessarily translate into efficacy in humans<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. Owing to the high morbidity and mortality rates of SARS and MERS, some of these antiviral drugs and immunomodulators have been used empirically or evaluated in uncontrolled trials<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR21">21</xref>
,<xref ref-type="bibr" rid="CR72">72</xref>
,<xref ref-type="bibr" rid="CR73">73</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR75">75</xref>
,<xref ref-type="bibr" rid="CR76">76</xref>
,<xref ref-type="bibr" rid="CR77">77</xref>
,<xref ref-type="bibr" rid="CR78">78</xref>
,<xref ref-type="bibr" rid="CR79">79</xref>
,<xref ref-type="bibr" rid="CR80">80</xref>
,<xref ref-type="bibr" rid="CR81">81</xref>
,<xref ref-type="bibr" rid="CR82">82</xref>
,<xref ref-type="bibr" rid="CR83">83</xref>
,<xref ref-type="bibr" rid="CR84">84</xref>
,<xref ref-type="bibr" rid="CR85">85</xref>
,<xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR88">88</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
,<xref ref-type="bibr" rid="CR90">90</xref>
</sup>
(<xref rid="Tab1" ref-type="table">Table 1</xref>
). Substantial efforts are underway to discover new therapeutic agents for CoV infections and these investigations are based on our understanding of the basic virology of CoVs. Importantly, treatment with these investigational therapies requires application of standard research treatment protocols and systematic clinical and virological data collection in controlled research trials, with the approval of the local ethics committee.<table-wrap id="Tab1"><label>Table 1</label>
<caption><title>Therapeutic interventions used in patients with SARS and MERS</title>
<p><xref rid="MOESM8" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Type of intervention</th>
<th>Therapeutic intervention</th>
<th>Treatment effects</th>
<th>Refs</th>
</tr>
</thead>
<tbody><tr><td align="center" colspan="4"><bold><italic>Treatments used for SARS patients</italic>
</bold>
</td>
</tr>
<tr><td rowspan="2">Antivirals</td>
<td>Ribavirin</td>
<td>No significant effect on clinical outcome</td>
<td><xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR21">21</xref>
</td>
</tr>
<tr><td>Ribavirin, lopinavir–ritonavir + corticosteroids</td>
<td>Patients who received ribavirin, lopinavir–ritonavir and a corticosteroid had lower 21-day ARDS and death rates than those who received ribavirin and a corticosteroid</td>
<td><xref ref-type="bibr" rid="CR76">76</xref>
,<xref ref-type="bibr" rid="CR77">77</xref>
</td>
</tr>
<tr><td>Interferon combination</td>
<td>Interferon alfa-1 + corticosteroid</td>
<td>Associated with improved oxygen saturation and more rapid resolution of radiographic lung opacities than systemic corticosteroid alone (uncontrolled study)</td>
<td><xref ref-type="bibr" rid="CR78">78</xref>
</td>
</tr>
<tr><td rowspan="2">Corticosteroids</td>
<td rowspan="2">Pulsed methylprednisolone</td>
<td>Associated with an increased 30-day mortality rate (adjusted OR = 26.0, 95% CI = 4.4–154.8). Disseminated fungal infection and avascular osteonecrosis occurred following prolonged systemic corticosteroid therapy</td>
<td><xref ref-type="bibr" rid="CR79">79</xref>
,<xref ref-type="bibr" rid="CR80">80</xref>
,<xref ref-type="bibr" rid="CR81">81</xref>
</td>
</tr>
<tr><td>A randomized, placebo-controlled study showed that plasma SARS-CoV RNA levels in weeks 2–3 of the illness were higher in patients given hydrocortisone (<italic>n</italic>
= 10) than those given normal saline (<italic>n</italic>
= 7) in the early phase of the illness, suggesting that early use of pulsed methylprednisolone might prolong viraemia</td>
<td><xref ref-type="bibr" rid="CR82">82</xref>
</td>
</tr>
<tr><td rowspan="2">Convalescent-phase plasma</td>
<td rowspan="2">Convalescent-phase plasma therapy</td>
<td>Has been used for severe respiratory tract infections including SARS and influenza. A systematic review and exploratory meta-analysis of patients with SARS or influenza treated with convalescent-phase plasma showed a reduction in mortality, but the treatment success was determined by its availability and timely administration</td>
<td><xref ref-type="bibr" rid="CR85">85</xref>
,<xref ref-type="bibr" rid="CR272">272</xref>
,<xref ref-type="bibr" rid="CR273">273</xref>
</td>
</tr>
<tr><td>Among 80 non-randomized SARS patients who were given convalescent-phase plasma, the discharge rate at day 22 was 58.3% for patients (<italic>n</italic>
= 48) treated within 14 days of illness onset versus 15.6% for those (<italic>n</italic>
= 32) treated beyond 14 days</td>
<td><xref ref-type="bibr" rid="CR83">83</xref>
,<xref ref-type="bibr" rid="CR84">84</xref>
</td>
</tr>
<tr><td align="center" colspan="4"><bold><italic>Treatments used for MERS patients</italic>
</bold>
</td>
</tr>
<tr><td rowspan="3">Combination of antivirals and interferons</td>
<td>Ribavirin + interferon alfa-2a or interferon alfa-2b</td>
<td>No significant effect on clinical outcome; case–control study showed significantly improved survival (14 out of 20 and 7 out of 24 in the treated and control groups, respectively; <italic>P</italic>
= 0.004) at 14 days, but not at 28 days</td>
<td><xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR88">88</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
</td>
</tr>
<tr><td>Ribavirin + interferon beta-1a</td>
<td>Retrospective analyses showed no significant effect on clinical outcome</td>
<td><xref ref-type="bibr" rid="CR89">89</xref>
</td>
</tr>
<tr><td>Ribavirin, lopinavir–ritonavir + interferon alfa-2a</td>
<td>Viraemia resolved 2 days after commencement of treatment in a patient with severe MERS</td>
<td><xref ref-type="bibr" rid="CR90">90</xref>
</td>
</tr>
<tr><td>Corticosteroids</td>
<td>Pulsed methylprednisolone</td>
<td>Patients with severe MERS who were treated with systemic corticosteroid with or without antivirals and interferons had no favourable response</td>
<td><xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR88">88</xref>
,<xref ref-type="bibr" rid="CR274">274</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>ARDS, acute respiratory distress syndrome; CI, confidence interval; CoV, coronavirus; MERS, Middle East respiratory syndrome; OR, odds ratio; SARS, severe acute respiratory syndrome.</p>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="Sec3"><title>Development of anti-CoV therapeutics</title>
<p id="Par22"><bold><italic>Key CoV targets for new drug development.</italic>
</bold>
Despite their high species diversity, CoVs share key genomic elements that are essential for the design of therapeutic targets (<xref rid="Fig1" ref-type="fig">Fig. 1</xref>
). The large replicase polyprotein 1a (pp1a) and pp1ab, which are encoded by the 5′-terminal open reading frame 1a/b (ORF1a/b), are cleaved by two viral proteases, the papain-like protease (PLpro) and the 3C-like protease (3CLpro), to produce non-structural proteins (NSPs) such as RNA-dependent RNA polymerase (RdRp) and helicase, which are involved in the transcription and replication of the virus<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR91">91</xref>
</sup>
(<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). Numerous enzyme inhibitors targeting these proteins have shown anti-CoV activity <italic>in vitro</italic>
.<fig id="Fig1"><label>Figure 1</label>
<caption><title>Genomes and structures of SARS-CoV and MERS-CoV.</title>
<p>The typical coronavirus (CoV) genome is a single-stranded, non-segmented RNA genome, which is approximately 26–32 kb. It contains 5′-methylated caps and 3′-polyadenylated tails and is arranged in the order of 5′, replicase genes, genes encoding structural proteins (spike glycoprotein (S), envelope protein (E), membrane protein (M) and nucleocapsid protein (N)), polyadenylated tail and then the 3′ end. The partially overlapping 5′-terminal open reading frame 1a/b (ORF1a/b) is within the 5′ two-thirds of the CoV genome and encodes the large replicase polyprotein 1a (pp1a) and pp1ab. These polyproteins are cleaved by papain-like cysteine protease (PLpro) and 3C-like serine protease (3CLpro) to produce non-structural proteins, including RNA-dependent RNA polymerase (RdRp) and helicase (Hel), which are important enzymes involved in the transcription and replication of CoVs. The 3′ one-third of the CoV genome encodes the structural proteins (S, E, M and N), which are essential for virus–cell-receptor binding and virion assembly, and other non-structural proteins and accessory proteins that may have immunomodulatory effects<sup><xref ref-type="bibr" rid="CR297">297</xref>
</sup>
. Particle image from Ref. <xref ref-type="bibr" rid="CR296">296</xref>
, Nature Publishing Group. MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome.</p>
<p><xref rid="MOESM6" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<graphic xlink:href="41573_2016_Article_BFnrd201537_Fig1_HTML" id="d29e1075"></graphic>
</fig>
<fig id="Fig2"><label>Figure 2</label>
<caption><title>Virus-based and host-based treatment options targeting the coronavirus replication cycle.</title>
<p>Binding between the receptor-binding domain on the S1 subunit of spike glycoprotein (S) and the host receptor triggers conformational changes in the S2 subunit of S. This leads to fusion of the viral and cell membranes. Coronaviruses (CoVs) enter the host cell using the endosomal pathway and/or the cell surface non-endosomal pathway. Endosomal cell entry of CoVs is facilitated by low pH and the pH-dependent endosomal cysteine protease cathepsins. S is activated and cleaved into the S1 and S2 subunits by other host proteases, such as transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D, which enables cell surface non-endosomal virus entry at the plasma membrane. Middle East respiratory syndrome (MERS)-CoV S is additionally activated by the serine endoprotease furin. CoVs then dissemble intracellularly to release the nucleocapsid and viral RNA into the cytoplasm for the translation of ORF1a/b into the large replicase polyprotein 1a (pp1a) and pp1ab and for the replication of genomic RNA. pp1a and pp1ab are cleaved by papain-like protease (PLpro) and 3C-like protease (3CLpro) to produce non-structural proteins (NSPs), including RNA-dependent RNA polymerase (RdRp) and helicase, which are involved in the transcription and replication of the virus. The NSPs produced by the cleavage of pp1a and pp1ab form the replication–transcription complex. Attachment of the hydrophobic domains of the CoV replication–transcription complex to the limiting membrane derived from the endoplasmic reticulum (ER) produces typical CoV replication structures including double-membrane vesicles and convoluted membranes. The full-length positive-strand genomic RNA is transcribed to form a full-length negative-strand template for synthesis of new genomic RNAs and overlapping subgenomic negative-strand templates. Subgenomic mRNAs are then synthesized and translated to produce the structural and accessory proteins. The helical nucleocapsid formed by the assembly of nucleocapsid protein (N) and genomic RNA interacts with the other structural proteins to form the assembled virion, which is then released by exocytosis into the extracellular compartment. Virus- and host-based treatment options are highlighted in red and blue, respectively. +, positive-strand RNA; −, negative-strand RNA; AP, accessory protein; CYP, cyclophilin; dec-RVKR-CMK, decanoyl-Arg-Val-Lys-Arg-chloromethylketone; DRACO, double-stranded RNA-activated caspase oligomerizer; E, envelope protein; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum Golgi intermediate compartment; ERK, extracellular signal-regulated kinase; M, membrane; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MPA, mycophenolic acid; mTOR, mammalian target of rapamycin; N, nucleocapsid protein; NAAE, N-(2-aminoethyl)-1-aziridine-ethanamine; NFAT, nuclear factor of activated T cells; ORF, open reading frame; PI3K, phosphoinositide 3-kinase; poly(I:C), polyinosinic:polycytidylic acid; RdRp, RNA-dependent RNA polymerase; S, spike glycoprotein; SARS-CoV, severe acute respiratory syndrome coronavirus; siRNA, small interfering RNA. *Only siRNAs that have been evaluated in published reports are included. siRNAs directed against other parts of the CoV genome would also be expected to diminish the accumulation or translation of genomic and all upstream subgenomic RNAs. Adapted with permission from Ref. <xref ref-type="bibr" rid="CR9">9</xref>
, American Society for Microbiology.</p>
<p><xref rid="MOESM7" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<graphic xlink:href="41573_2016_Article_BFnrd201537_Fig2_HTML" id="d29e1095"></graphic>
</fig>
</p>
<p id="Par23">The surface structural <xref rid="Glos2" ref-type="list">spike glycoprotein (S)</xref>
is of particular interest for antiviral development because of its critical role in the virus–cell receptor interaction. S is composed of the amino-terminal receptor-binding S1 and carboxy-terminal membrane fusion S2 subunits. Cleavage at the protease site at the S1–S2 junction is required to activate membrane fusion, virus entry and <xref rid="Glos3" ref-type="list">syncytium</xref>
formation<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. Binding of the S1 subunit receptor-binding domain (RBD) to the host receptor triggers conformational changes in the S2 subunit (the stalk region of S) to bring the viral and cell membranes into close proximity and enable fusion<sup><xref ref-type="bibr" rid="CR92">92</xref>
</sup>
. Monoclonal antibodies (mAbs) against the S1 subunit RBD and fusion inhibitors targeting the S2 subunit have potent anti-CoV activity <italic>in vitro</italic>
and/or <italic>in vivo</italic>
<sup><xref ref-type="bibr" rid="CR92">92</xref>
,<xref ref-type="bibr" rid="CR93">93</xref>
,<xref ref-type="bibr" rid="CR94">94</xref>
,<xref ref-type="bibr" rid="CR95">95</xref>
,<xref ref-type="bibr" rid="CR96">96</xref>
,<xref ref-type="bibr" rid="CR97">97</xref>
,<xref ref-type="bibr" rid="CR98">98</xref>
,<xref ref-type="bibr" rid="CR99">99</xref>
,<xref ref-type="bibr" rid="CR100">100</xref>
</sup>
. The key functional host receptors utilized by human pathogenic CoVs include angiotensin-converting enzyme 2 (ACE2; used by SARS-CoV and human CoV (HCoV)-NL63), dipeptidyl peptidase 4 (DPP4; used by MERS-CoV), aminopeptidase N (used by HCoV-229E), and <italic>O</italic>
-acetylated sialic acid (used by HCoV-OC43 and HCoV-HKU1)<sup><xref ref-type="bibr" rid="CR101">101</xref>
,<xref ref-type="bibr" rid="CR102">102</xref>
,<xref ref-type="bibr" rid="CR103">103</xref>
,<xref ref-type="bibr" rid="CR104">104</xref>
,<xref ref-type="bibr" rid="CR105">105</xref>
,<xref ref-type="bibr" rid="CR106">106</xref>
</sup>
. The host receptor is important in determining the pathogenicity, tissue tropism and host range of the virus. mAbs or agents that target the host receptor are potential anti-CoV agents so long as they do not induce immunopathological effects in animal models.</p>
<p id="Par24">CoVs enter the host cell using the endosomal pathway and/or the cell surface non-endosomal pathway<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
(<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). Low pH and the pH-dependent endosomal cysteine protease cathepsins help to overcome the energetically unfavourable membrane fusion reaction and facilitate endosomal cell entry of CoVs<sup><xref ref-type="bibr" rid="CR107">107</xref>
,<xref ref-type="bibr" rid="CR108">108</xref>
</sup>
. Other host proteases, such as transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D (also known as airway trypsin-like protease), cleave S into the S1 and S2 subunits to activate S for cell surface non-endosomal virus entry at the plasma membrane<sup><xref ref-type="bibr" rid="CR109">109</xref>
</sup>
. Inhibitors of these proteases can abrogate this proteolytic cleavage and partially block cell entry<sup><xref ref-type="bibr" rid="CR109">109</xref>
</sup>
. MERS-CoV S is also activated by furin, a serine endoprotease that has been implicated in the processing of fusion proteins and cell entry of other RNA viruses, including HIV, avian influenza A/H5N1 virus, Ebola virus, Marburg virus and flaviviruses<sup><xref ref-type="bibr" rid="CR110">110</xref>
</sup>
. Furin is also involved in MERS-CoV S1/S2 cleavage during egress from the infected cell<sup><xref ref-type="bibr" rid="CR110">110</xref>
</sup>
. Monotherapy and/or combinatorial treatment with inhibitors of host proteases involved in the various cell entry pathways have potent anti-CoV activity <italic>in vitro</italic>
and should be further evaluated in animal studies<sup><xref ref-type="bibr" rid="CR109">109</xref>
,<xref ref-type="bibr" rid="CR111">111</xref>
</sup>
.</p>
<p id="Par25">CoVs disassemble inside the host cell and release the nucleocapsid and viral RNA into the cytoplasm, after which ORF1a/b is translated into pp1a and pp1ab, and the genomic RNA is replicated<sup><xref ref-type="bibr" rid="CR91">91</xref>
</sup>
. The numerous NSPs produced by the cleavage of pp1a and pp1ab form the replication–transcription complex. Attachment of the hydrophobic domains of the CoV replication–transcription complex to the limiting membrane derived from the endoplasmic reticulum produces typical CoV replication structures including double-membrane vesicles (DMVs) and convoluted membranes<sup><xref ref-type="bibr" rid="CR112">112</xref>
,<xref ref-type="bibr" rid="CR113">113</xref>
</sup>
. Novel agents, such as K22, that target membrane-bound CoV RNA synthesis inhibit DMV formation of a broad range of human and animal CoVs<sup><xref ref-type="bibr" rid="CR112">112</xref>
</sup>
. The full-length positive strand of genomic RNA is transcribed to form a full-length negative-strand template for the synthesis of new genomic RNAs and overlapping subgenomic negative-strand templates<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR91">91</xref>
</sup>
. Subgenomic mRNAs are then synthesized and translated to produce the structural and accessory proteins<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR91">91</xref>
</sup>
. The helical nucleocapsid, formed by the assembly of nucleocapsid protein (N) and genomic RNA, then interacts with S, envelope protein (E), and membrane protein (M) to form the assembled virion<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. The virion is released into the extracellular compartment by exocytosis and the viral replication cycle is repeated<sup><xref ref-type="bibr" rid="CR9">9</xref>
</sup>
. Small interfering RNAs (siRNAs) targeting these structural genes could be useful in the treatment of CoV infections, and further optimization of the <italic>in vivo</italic>
delivery of siRNAs may enable their clinical use.</p>
<p id="Par26"><bold><italic>Approaches to anti-CoV drug screening.</italic>
</bold>
The only two human-pathogenic CoVs known before the SARS epidemic were HCoV-229E and HCoV-OC43, which usually cause self-limiting upper respiratory tract infections<sup><xref ref-type="bibr" rid="CR2">2</xref>
</sup>
. Therefore, researchers and research facilities, especially those involved in antiviral development, were underprepared when SARS-CoV suddenly emerged in 2003. Subsequently, three general approaches were used to discover potential anti-CoV treatment options for human-pathogenic CoVs — especially SARS-CoV and the emerging MERS-CoV — that are associated with more severe disease than the other HCoVs are<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR114">114</xref>
,<xref ref-type="bibr" rid="CR115">115</xref>
</sup>
.</p>
<p id="Par27">The first approach to drug discovery is to test existing broad-spectrum antiviral drugs that have been used to treat other viral infections by using standard assays that measure the effects of these drugs on the cytopathicity, virus yield and plaque formation of live and/or pseudotyped CoVs. Examples of drugs identified using this approach include interferon alfa, interferon beta, interferon gamma, ribavirin and inhibitors of cyclophilin<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR116">116</xref>
,<xref ref-type="bibr" rid="CR117">117</xref>
,<xref ref-type="bibr" rid="CR118">118</xref>
,<xref ref-type="bibr" rid="CR119">119</xref>
,<xref ref-type="bibr" rid="CR120">120</xref>
,<xref ref-type="bibr" rid="CR121">121</xref>
,<xref ref-type="bibr" rid="CR122">122</xref>
</sup>
. These drugs have the obvious advantage of being readily available with known pharmacokinetic and pharmacodynamic properties, side effects and dosing regimens. However, they do not have specific anti-CoV effects and may be associated with severe adverse effects.</p>
<p id="Par28">The second anti-CoV drug discovery approach involves the screening of chemical libraries comprising large numbers of existing compounds or databases that contain information on transcriptional signatures in different cell lines<sup><xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR124">124</xref>
,<xref ref-type="bibr" rid="CR125">125</xref>
,<xref ref-type="bibr" rid="CR126">126</xref>
,<xref ref-type="bibr" rid="CR127">127</xref>
</sup>
. This approach provides rapid, high-throughput screening of many readily available compounds that can then be further evaluated by antiviral assays. Various classes of drugs have been identified in these drug repurposing programmes, including many that have important physiological and/or immunological effects such as those that affect neurotransmitter regulation, the oestrogen receptor, kinase signalling, lipid or sterol metabolism, protein processing and DNA synthesis or repair<sup><xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR124">124</xref>
,<xref ref-type="bibr" rid="CR125">125</xref>
,<xref ref-type="bibr" rid="CR126">126</xref>
,<xref ref-type="bibr" rid="CR127">127</xref>
</sup>
. The major disadvantage of this approach is that although many of the identified drugs exhibit anti-CoV activities <italic>in vitro</italic>
, most are not clinically useful because they are either associated with immunosuppressive effects or they have anti-CoV half-maximal effective concentration (EC<sub>50</sub>
) values that markedly exceed the peak serum concentration (C<sub>max</sub>
) levels that are achievable at therapeutic dosages. A notable exception, which was found to be effective in a non-human primate model and in non-randomized clinical trials, is the anti-HIV protease inhibitor lopinavir–ritonavir<sup><xref ref-type="bibr" rid="CR76">76</xref>
,<xref ref-type="bibr" rid="CR77">77</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
</sup>
(<xref rid="Tab1" ref-type="table">Table 1</xref>
).</p>
<p id="Par29">The third approach for anti-CoV drug discovery involves the <italic>de novo</italic>
development of novel, specific agents based on the genomic and biophysical understanding of the individual CoVs. Examples include siRNA molecules or inhibitors that target specific viral enzymes involved in the viral replication cycle, mAbs that target the host receptor, inhibitors of host cellular proteases, inhibitors of virus endocytosis by the host cell, human or humanized mAbs that target the S1 subunit RBD and antiviral peptides that target the S2 subunit (<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). Although most of these drugs have potent <italic>in vitro</italic>
and/or <italic>in vivo</italic>
anti-CoV activity, their pharmacokinetic and pharmacodynamic properties and side-effect profiles have yet to be evaluated in animal and human trials. Furthermore, the development of these candidate drugs into clinically useful therapeutic options with reliable delivery modes for patients usually takes years.</p>
<p id="Par30">Overall, these three drug discovery approaches are often used together during emerging CoV outbreaks to identify candidate drug compounds that can be broadly classified into virus-based and host-based treatment options.</p>
</sec>
<sec id="Sec4"><title>Virus-based anti-CoV treatment options</title>
<p id="Par31"><bold><italic>Viral nucleosides, nucleotides and nucleic acids.</italic>
</bold>
Nucleosides and nucleotides are the building blocks of viral nucleic acids (<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). Drugs that target nucleosides or nucleotides and/or viral nucleic acids generally have broad-spectrum activity against a wide range of CoVs and other viruses (<xref rid="Tab2" ref-type="table">Table 2</xref>
). Mycophenolate mofetil is an anti-rejection drug that inhibits inosine monophosphate dehydrogenase and the synthesis of guanine monophosphate<sup><xref ref-type="bibr" rid="CR122">122</xref>
</sup>
. The active compound, mycophenolic acid, exhibits antiviral activity <italic>in vitro</italic>
against various viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV) and arboviruses<sup><xref ref-type="bibr" rid="CR122">122</xref>
</sup>
. Mycophenolic acid was identified as a potential anti-MERS-CoV drug using high-throughput screening and has potent anti-MERS-CoV activity <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR122">122</xref>
</sup>
. However, a subsequent study in a non-human primate model showed that MERS-CoV-infected common marmosets treated with mycophenolate mofetil had a worse outcome with more severe disease and higher viral loads in necropsied lung and extrapulmonary tissues than untreated animals did<sup><xref ref-type="bibr" rid="CR128">128</xref>
</sup>
. Renal transplant recipients who were on maintenance mycophenolate mofetil therapy also developed severe or fatal MERS<sup><xref ref-type="bibr" rid="CR129">129</xref>
,<xref ref-type="bibr" rid="CR130">130</xref>
</sup>
. Thus, the usual dosage of mycophenolate mofetil monotherapy is unlikely to be useful for prophylaxis or treatment of CoV infections.<table-wrap id="Tab2"><label>Table 2</label>
<caption><title>Representative virus-based treatment strategies for CoV infections</title>
<p><xref rid="MOESM9" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Targeted viral components</th>
<th>Examples</th>
<th>Mechanism of action</th>
<th>Status</th>
<th>Comments</th>
<th>Refs</th>
</tr>
</thead>
<tbody><tr><td align="center" colspan="6"><bold><italic>Viral nucleic acids</italic>
</bold>
</td>
</tr>
<tr><td>Nucleosides and/or nucleotides</td>
<td>Mycophenolic acid</td>
<td>Inhibitor of IMPDH and guanine monophosphate synthesis</td>
<td>Marketed</td>
<td><p>• Broad spectrum: MERS-CoV, HBV, HCV, arboviruses (JEV, WNV, YFV, dengue virus and CHIKV)</p>
<p>• Worsened outcome in MERS-CoV-infected common marmosets</p>
<p>• Unlikely to be useful as monotherapy, but combinatorial therapy with interferon beta-1b is synergistic <italic>in vitro</italic>
</p>
</td>
<td><xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR192">192</xref>
</td>
</tr>
<tr><td>mRNA</td>
<td>Ribozyme</td>
<td>An antisense RNA with catalytic activity that specifically recognizes the base sequence GUC in the loop region on the mRNA of CoVs</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR131">131</xref>
</td>
</tr>
<tr><td>Host cell membrane-bound viral replication complex</td>
<td>K22</td>
<td>Inhibitor of membrane-bound RNA synthesis and double membrane vesicle formation</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E and animal CoVs</p>
<p>• No animal or human data available</p>
</td>
<td><xref ref-type="bibr" rid="CR112">112</xref>
</td>
</tr>
<tr><td>Long viral dsRNA</td>
<td>DRACO</td>
<td>A chimeric protein with a viral dsRNA-binding domain and a pro-apoptotic domain that selectively induces apoptosis in cells containing viral dsRNA</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: adenoviruses, arenaviruses, bunyaviruses, dengue virus, IAV, picornaviruses, rhinoviruses and reoviruses</p>
<p>• Anti-CoV activity has yet to be demonstrated</p>
</td>
<td><xref ref-type="bibr" rid="CR132">132</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Viral enzymes</italic>
</bold>
</td>
</tr>
<tr><td>PLpro</td>
<td>GRL0617, compound 4</td>
<td>Inhibitors of PLpro activity</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• No animal or human data available</p>
</td>
<td><xref ref-type="bibr" rid="CR137">137</xref>
,<xref ref-type="bibr" rid="CR138">138</xref>
,<xref ref-type="bibr" rid="CR139">139</xref>
,<xref ref-type="bibr" rid="CR140">140</xref>
</td>
</tr>
<tr><td>3CLpro</td>
<td>Lopinavir, N3, CE-5 and GRL-001</td>
<td>Inhibitors of 3CLpro activity</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and animal CoVs</p>
<p>• Marketed: lopinavir–ritonavir</p>
<p>• Improved outcome of MERS-CoV-infected common marmosets</p>
<p>• Improved outcome of SARS patients in non-randomized trials</p>
</td>
<td><xref ref-type="bibr" rid="CR76">76</xref>
,<xref ref-type="bibr" rid="CR77">77</xref>
,<xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR143">143</xref>
,<xref ref-type="bibr" rid="CR144">144</xref>
,<xref ref-type="bibr" rid="CR145">145</xref>
,<xref ref-type="bibr" rid="CR146">146</xref>
,<xref ref-type="bibr" rid="CR275">275</xref>
,<xref ref-type="bibr" rid="CR276">276</xref>
</td>
</tr>
<tr><td rowspan="4">RdRp</td>
<td>Ribavirin</td>
<td>Guanosine analogue that inhibits viral RNA synthesis and mRNA capping</td>
<td>Marketed</td>
<td><p>• Broad spectrum: many viral infections, especially SARS, MERS, RSV, HCV and viral haemorrhagic fevers</p>
<p>• Active against SARS-CoV and MERS-CoV at high doses <italic>in vitro</italic>
</p>
<p>• Benefits in SARS and MERS patients are uncertain</p>
<p>• Side effects are common and may be severe with high-dose reigmens</p>
</td>
<td><xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR21">21</xref>
,<xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR88">88</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
,<xref ref-type="bibr" rid="CR117">117</xref>
,<xref ref-type="bibr" rid="CR277">277</xref>
,<xref ref-type="bibr" rid="CR278">278</xref>
,<xref ref-type="bibr" rid="CR279">279</xref>
,<xref ref-type="bibr" rid="CR280">280</xref>
</td>
</tr>
<tr><td>BCX4430</td>
<td>Adenosine analogue that acts as a non-obligate RNA chain terminator to inhibit viral RNA polymerase function</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV, IAV, filoviruses, togaviruses, bunyaviruses, arenaviruses, paramyxoviruses, picornaviruses and flaviviruses</p>
<p>• No animal or human data are available for CoVs</p>
</td>
<td><xref ref-type="bibr" rid="CR149">149</xref>
</td>
</tr>
<tr><td>Fleximer nucleoside analogues of acyclovir</td>
<td>Doubly flexible nucleoside analogues based on the acyclic sugar scaffold of acyclovir and the flex-base moiety in fleximers that inhibit RdRp</td>
<td>Preclinical</td>
<td><p>• Active against MERS-CoV and HCoV-NL63</p>
<p>• Further modification of existing nucleoside analogues with different fleximers is possible</p>
<p>• No animal or human data available</p>
</td>
<td><xref ref-type="bibr" rid="CR150">150</xref>
</td>
</tr>
<tr><td>siRNA*</td>
<td>Short chains of dsRNA that interfere with the expression of RdRp</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR151">151</xref>
,<xref ref-type="bibr" rid="CR152">152</xref>
</td>
</tr>
<tr><td rowspan="2">Helicase</td>
<td>Bananins and 5-hydroxychromone derivatives</td>
<td>Inhibits helicase unwinding and ATPase activities</td>
<td>Preclinical</td>
<td><p>• Possibly broad spectrum: helicase is relatively conserved among CoVs</p>
<p>• High risk of toxicity</p>
</td>
<td><xref ref-type="bibr" rid="CR153">153</xref>
,<xref ref-type="bibr" rid="CR154">154</xref>
</td>
</tr>
<tr><td>SSYA10-001 and ADKs</td>
<td>Inhibits helicase unwinding without affecting ATPase activity</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV and animal CoVs</p>
<p>• Likely to be less toxic than bananins and 5-hydroxychromone derivatives</p>
</td>
<td><xref ref-type="bibr" rid="CR155">155</xref>
,<xref ref-type="bibr" rid="CR156">156</xref>
,<xref ref-type="bibr" rid="CR281">281</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Viral spike glycoprotein</italic>
</bold>
</td>
</tr>
<tr><td>RBD of the S1 subunit of S</td>
<td>MERS-4, MERS-27, m336, m337, m338, REGN3051 and REGN3048 mAbs</td>
<td>mAbs against the RBD of the S1 subunit that block virus–host cell binding</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• May reduce the need for convalescent-phase plasma therapy</p>
<p>• Protective effects demonstrated in animal models</p>
</td>
<td><xref ref-type="bibr" rid="CR94">94</xref>
,<xref ref-type="bibr" rid="CR95">95</xref>
,<xref ref-type="bibr" rid="CR96">96</xref>
,<xref ref-type="bibr" rid="CR97">97</xref>
,<xref ref-type="bibr" rid="CR100">100</xref>
,<xref ref-type="bibr" rid="CR160">160</xref>
,<xref ref-type="bibr" rid="CR161">161</xref>
,<xref ref-type="bibr" rid="CR162">162</xref>
</td>
</tr>
<tr><td>S2 subunit of S</td>
<td>HR2P and P1 peptides</td>
<td>Antiviral peptides that inhibit fusion of S with host cell receptor</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Enfuvirtide, an anti-HIV antiviral peptide fusion inhibitor, has been successfully marketed</p>
</td>
<td><xref ref-type="bibr" rid="CR92">92</xref>
,<xref ref-type="bibr" rid="CR93">93</xref>
,<xref ref-type="bibr" rid="CR99">99</xref>
,<xref ref-type="bibr" rid="CR160">160</xref>
,<xref ref-type="bibr" rid="CR161">161</xref>
,<xref ref-type="bibr" rid="CR162">162</xref>
</td>
</tr>
<tr><td>Oligosaccharides on S</td>
<td>Griffithsin</td>
<td>A carbohydrate-binding agent that specifically binds to oligosaccharides on S, thereby blocking virus–host cell binding</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HIV, HCV and Ebola virus</p>
<p>• Well tolerated in rodents</p>
</td>
<td><xref ref-type="bibr" rid="CR173">173</xref>
,<xref ref-type="bibr" rid="CR174">174</xref>
</td>
</tr>
<tr><td>S expression</td>
<td>siRNA*</td>
<td>Short chains of dsRNA that interfere with the expression of SARS-CoV S</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• SARS-CoV-infected rhesus macaques had better clinical, virological, and histological parameters</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR169">169</xref>
,<xref ref-type="bibr" rid="CR170">170</xref>
,<xref ref-type="bibr" rid="CR171">171</xref>
,<xref ref-type="bibr" rid="CR172">172</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Viral envelope, membrane, nucleocapsid and accessory proteins</italic>
</bold>
</td>
</tr>
<tr><td rowspan="2">E</td>
<td>siRNA*</td>
<td>Short chains of dsRNA that interfere with the expression of SARS-CoV E</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR179">179</xref>
</td>
</tr>
<tr><td>Hexamethylene amiloride</td>
<td>Viroporin inhibitor that inhibits the ion channel activity of CoV E</td>
<td>Preclinical</td>
<td><p>• Inhibited ion channel activities of SARS-CoV, HCoV-229E and some animal CoVs</p>
<p>• Analogue of the potassium-sparing diuretic drug amiloride</p>
</td>
<td><xref ref-type="bibr" rid="CR181">181</xref>
,<xref ref-type="bibr" rid="CR182">182</xref>
</td>
</tr>
<tr><td>M</td>
<td>siRNA*</td>
<td>Short chains of dsRNA that interfere with the expression of SARS-CoV M</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR179">179</xref>
</td>
</tr>
<tr><td>N</td>
<td>PJ34, intrabodies<sup>‡</sup>
and siRNA*</td>
<td>Reduces the RNA-binding affinity of N and viral replication</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR179">179</xref>
,<xref ref-type="bibr" rid="CR183">183</xref>
,<xref ref-type="bibr" rid="CR282">282</xref>
</td>
</tr>
<tr><td>Accessory proteins</td>
<td>siRNA*</td>
<td>Short chains of dsRNA that interfere with the expression of proteins from SARS-CoV ORF3a, ORF7a and ORF7b</td>
<td>Preclinical</td>
<td><p>• Narrow spectrum</p>
<p>• Optimal delivery method in humans is uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR180">180</xref>
</td>
</tr>
<tr><td>Lipid membrane</td>
<td>LJ001 and JL103</td>
<td>Membrane-binding photosensitizers that induce singlet oxygen modifications of specific phospholipids</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: enveloped viruses (IAV, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses and HIV-1)</p>
<p>• Anti-CoV activity has yet to be demonstrated</p>
</td>
<td><xref ref-type="bibr" rid="CR184">184</xref>
,<xref ref-type="bibr" rid="CR185">185</xref>
,<xref ref-type="bibr" rid="CR186">186</xref>
,<xref ref-type="bibr" rid="CR187">187</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>3CLpro, 3C-like protease; ADK, aryl diketoacid; CHIKV, Chikungunya virus; CoV, coronavirus; DRACO, double-stranded RNA activated caspase oligomerizer; dsRNA, double-stranded RNA; E, envelope protein; HBV, hepatitis B virus; HCoV, human coronavirus; HCV, hepatitis C virus; IAV, influenza A virus; IMPDH, inosine-monophosphate dehydrogenase; JEV, Japanese encephalitis virus; M, membrane protein; mAb, monoclonal antibody; MERS, Middle East respiratory syndrome; N, nucleocapsid protein; ORF, open reading frame; PLpro, papain-like protease; RBD, receptor-binding domain; RdRp, RNA-dependent RNA polymerase; RSV, respiratory syncytial virus; S, spike glycoprotein; SARS, severe acute respiratory syndrome; siRNA, small interfering RNA; WNV, West Nile virus; YFV, yellow fever virus.</p>
<p>*Only siRNAs that have been evaluated in published reports are included. siRNAs directed against other parts of the CoV genome would also be expected to diminish the accumulation or translation of genomic and upstream subgenomic RNAs.</p>
<p><sup>‡</sup>
Intrabodies are antibodies that work within the cell to bind to intracellular proteins.</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par32">Ribozymes (also known as catalytic RNA or RNA enzymes) are RNA molecules that catalyse specific biochemical reactions. A chimeric DNA–RNA hammerhead ribozyme that specifically recognizes the base sequence GUC, which is present in the loop region of SARS-CoV mRNA, substantially reduces the expression of recombinant SARS-CoV RNA <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR131">131</xref>
</sup>
. However, ribozymes are rapidly degraded <italic>in vivo</italic>
and delivery methods would have to be optimized in humans before ribozymes could become clinically useful.</p>
<p id="Par33">Agents targeting the specific host cell membrane-bound CoV replication complex have also been investigated. One such compound, K22, inhibits membrane-bound CoV RNA synthesis and is active against a broad range of CoVs <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR112">112</xref>
</sup>
. In cell culture, K22 exerts potent anti-CoV activity during an early step of the viral replication cycle and impairs formation of DMVs<sup><xref ref-type="bibr" rid="CR112">112</xref>
</sup>
. HCoV-229E escape mutants that are resistant to K22 have substitutions in the potential membrane-spanning domains in nsp6, a membrane-spanning integral component of the CoV replication complex that is involved in DMV formation, including nsp6<sup>H121L</sup>
and nsp6<sup>M159V</sup>
(Ref. <xref ref-type="bibr" rid="CR112">112</xref>
). The emergence of K22 resistance should be monitored in subsequent <italic>in vivo</italic>
studies.</p>
<p id="Par34">Recently, a new class of broad-spectrum antivirals that targets long viral double-stranded RNA (dsRNA) has been reported. For example, dsRNA-activated caspase oligomerizer (DRACO) is a chimeric protein with a viral dsRNA-binding domain and a pro-apoptotic domain that selectively induces apoptosis in cells that contain viral dsRNA but spares uninfected host cells<sup><xref ref-type="bibr" rid="CR132">132</xref>
</sup>
. DRACO is active against many RNA viruses <italic>in vitro</italic>
and/or <italic>in vivo</italic>
<sup><xref ref-type="bibr" rid="CR132">132</xref>
</sup>
. If an effective mode of DRACO delivery can be achieved, a broad-spectrum anti-CoV drug that targets highly conserved CoV RNA sequences might become a reality.</p>
<p id="Par35"><bold><italic>Viral enzymes.</italic>
</bold>
All of the major enzymes and proteins of CoVs that are involved in viral replication are potentially druggable targets (<xref rid="Tab2" ref-type="table">Table 2</xref>
). The SARS-CoV and MERS-CoV PLpro enzymes exhibit proteolytic, deubiquitylating and deISGylating activities<sup><xref ref-type="bibr" rid="CR133">133</xref>
,<xref ref-type="bibr" rid="CR134">134</xref>
,<xref ref-type="bibr" rid="CR135">135</xref>
</sup>
. Crystallography has facilitated the characterization of these PLpro enzymes and the identification of PLpro inhibitors<sup><xref ref-type="bibr" rid="CR136">136</xref>
</sup>
. Numerous SARS-CoV PLpro inhibitors belonging to different classes have been identified, including small-molecule inhibitors, thiopurine compounds, natural products, zinc ion and zinc conjugate inhibitors and naphthalene inhibitors<sup><xref ref-type="bibr" rid="CR137">137</xref>
</sup>
. However, some of these drugs only inhibit the enzymatic activities of PLpro without inhibiting viral replication, or <italic>vice versa</italic>
<sup><xref ref-type="bibr" rid="CR137">137</xref>
,<xref ref-type="bibr" rid="CR138">138</xref>
,<xref ref-type="bibr" rid="CR139">139</xref>
</sup>
. None has been validated in animal or human studies<sup><xref ref-type="bibr" rid="CR137">137</xref>
,<xref ref-type="bibr" rid="CR138">138</xref>
</sup>
. Furthermore, most PLpro inhibitors have narrow-spectrum activity because of the structural differences among the PLpro enzymes of different CoVs<sup><xref ref-type="bibr" rid="CR140">140</xref>
,<xref ref-type="bibr" rid="CR141">141</xref>
</sup>
. For example, most SARS-CoV PLpro inhibitors are inactive against MERS-CoV because of the structurally different, flexible blocking loop 2 (BL2) domains in the PLpro enzymes of SARS-CoV and MERS-CoV<sup><xref ref-type="bibr" rid="CR140">140</xref>
</sup>
.</p>
<p id="Par36">3CLpro is the other major CoV protease that cleaves the large replicase polyproteins during viral replication. SARS-CoV 3CLpro can be targeted by numerous classes of protease inhibitors, including zinc or mercury conjugates, C2-symmetric diols, peptidomimetic-α,β-unsaturated esters, anilides, benzotriazole, <italic>N</italic>
-phenyl-2-acetamide, biphenyl sulfone, glutamic acid and glutamine peptides with a trifluoromethylketone group, pyrimidinone and pyrazole analogues<sup><xref ref-type="bibr" rid="CR142">142</xref>
</sup>
. Some of these 3CLpro inhibitors demonstrate broad-spectrum <italic>in vitro</italic>
activities against CoVs with highly similar key residues for substrate recognition at their 3CLpro enzymes<sup><xref ref-type="bibr" rid="CR143">143</xref>
,<xref ref-type="bibr" rid="CR144">144</xref>
</sup>
. Among these 3CLpro inhibitors, the most readily available one is lopinavir, a protease inhibitor used to treat HIV infections that is usually marketed as a ritonavir-boosted form (lopinavir–ritonavir). Lopinavir and/or lopinavir–ritonavir have anti-CoV activity <italic>in vitro</italic>
, as well as in MERS-CoV-infected non-human primates and in non-randomized trials of SARS patients<sup><xref ref-type="bibr" rid="CR76">76</xref>
,<xref ref-type="bibr" rid="CR77">77</xref>
,<xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR145">145</xref>
</sup>
. It is postulated that the 3CLpro-inhibiting activity of lopinavir–ritonavir contributes at least partially to its anti-CoV effects<sup><xref ref-type="bibr" rid="CR146">146</xref>
</sup>
. It remains to be seen if resistance emerges, as it has in patients with HIV infection, when lopinavir–ritonavir is routinely used to treat CoV infections.</p>
<p id="Par37">RdRp is an essential part of the CoV replication–transcription complex and is involved in the production of genomic and subgenomic RNAs. Ribavirin is a guanosine analogue with broad-spectrum antiviral activity and has been used in the treatment of severe respiratory syncytial virus infection, HCV infection and viral haemorrhagic fevers. Its exact mechanism of action is undetermined, but inhibition of mRNA capping and induction of mutations in RNA-dependent viral replication are considered to be important for RNA viruses, including CoVs<sup><xref ref-type="bibr" rid="CR147">147</xref>
</sup>
. High-dose ribavirin has been used to treat SARS patients, but the benefits were unclear<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR10">10</xref>
,<xref ref-type="bibr" rid="CR21">21</xref>
,<xref ref-type="bibr" rid="CR72">72</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR75">75</xref>
,<xref ref-type="bibr" rid="CR117">117</xref>
</sup>
. It exhibits moderate anti-MERS-CoV activity at high doses <italic>in vitro</italic>
and in MERS-CoV-infected rhesus macaques, but there was no obvious survival benefit in small cohorts of MERS patients<sup><xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR88">88</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
,<xref ref-type="bibr" rid="CR121">121</xref>
,<xref ref-type="bibr" rid="CR148">148</xref>
</sup>
. Moreover, the severe side effects associated with the use of high-dose ribavirin limit its clinical application in patients with severe CoV infections<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
</sup>
. Recently, a novel adenosine analogue, BCX4430 (Immucillin-A), was developed<sup><xref ref-type="bibr" rid="CR149">149</xref>
</sup>
. It acts as a non-obligate RNA chain terminator to inhibit viral RNA polymerases of a wide range of RNA viruses, including CoVs such as SARS-CoV and MERS-CoV as well as filoviruses such as Ebola and Marburg viruses<sup><xref ref-type="bibr" rid="CR149">149</xref>
</sup>
. Its development for human use has been fast-tracked to increase the number of treatment options for the recent Ebola virus epidemic in West Africa. Existing nucleoside analogues, such as acyclovir, could be modified by incorporating fleximers, which have increased binding affinity and can overcome resistance caused by point mutations in biologically important binding sites<sup><xref ref-type="bibr" rid="CR150">150</xref>
</sup>
. These acyclic fleximer nucleoside analogues inhibit MERS-CoV and HCoV-NL63 <italic>in vitro</italic>
at micromolar concentrations<sup><xref ref-type="bibr" rid="CR150">150</xref>
</sup>
. Notably, resistance to nucleoside analogues due to mutations in RdRp has been reported for other RNA viruses, and should be monitored when these agents are used to treat CoV infections. In addition to nucleoside analogues, siRNA molecules targeting SARS-CoV RdRp have been used to inhibit SARS-CoV <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR151">151</xref>
,<xref ref-type="bibr" rid="CR152">152</xref>
</sup>
.</p>
<p id="Par38">Helicase catalyses the unwinding of duplex oligonucleotides into single strands in an ATP-dependent reaction during the CoV replication cycle. Helicase inhibitors are attractive anti-CoV treatment options because the helicases of different CoVs are highly homologous. Based on their mechanisms of action, CoV helicase inhibitors can be broadly categorized into two groups. The first group includes bananins and 5-hydroxychromone derivatives, which inhibit the unwinding and ATPase activity of SARS-CoV helicase, resulting in inhibition of viral replication <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR153">153</xref>
,<xref ref-type="bibr" rid="CR154">154</xref>
</sup>
. However, the toxicity resulting from the inhibition of cellular ATPases or kinases by these compounds has limited their development for human use. The second group of CoV helicase inhibitors includes compounds that selectively inhibit the unwinding activity but not the ATPase activity of CoV helicase. An example is SSYA10-001, a triazole that inhibits a broad range of CoVs, including SARS-CoV, MERS-CoV and mouse hepatitis virus<sup><xref ref-type="bibr" rid="CR155">155</xref>
,<xref ref-type="bibr" rid="CR156">156</xref>
</sup>
. The toxicity of SSYA10-001 should be evaluated in animal models.</p>
<p id="Par39"><bold><italic>Viral spike glycoprotein.</italic>
</bold>
The membrane-anchored glycoprotein, S, is a major immunogenic antigen and is essential for the interaction between the virus and the host cell receptor (<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). Adoptive transfer of sera containing anti-MERS-CoV-S antibodies blocked virus attachment and accelerated viral clearance from the lungs of MERS-CoV infected BALB/c mice that were recently transduced by adenoviral vectors expressing human DPP4 (Ref. <xref ref-type="bibr" rid="CR157">157</xref>
) (<xref rid="Tab2" ref-type="table">Table 2</xref>
). Small cohorts of SARS patients who received <xref rid="Glos4" ref-type="list">convalescent-phase plasma</xref>
containing neutralizing antibodies that probably targeted CoV S had significantly higher discharge rates by 3 weeks after symptom onset and a lower mortality rate<sup><xref ref-type="bibr" rid="CR83">83</xref>
,<xref ref-type="bibr" rid="CR84">84</xref>
</sup>
. However, the use of convalescent-phase plasma therapy during emerging CoV outbreaks is limited by the good will of convalescent patients with high serum neutralizing antibody titres. Disease worsening associated with immune enhancement that results from treatment with products containing low antibody titres has been reported in cell line and animal studies<sup><xref ref-type="bibr" rid="CR158">158</xref>
,<xref ref-type="bibr" rid="CR159">159</xref>
</sup>
. To overcome these problems, mAbs targeting different regions of SARS-CoV S have been generated by immunization of human immunoglobulin transgenic mice, cloning of small chain variable regions from naive and convalescent patients as well as from immortalization of convalescent S-specific B cells<sup><xref ref-type="bibr" rid="CR160">160</xref>
</sup>
. Most of these mAbs target specific epitopes on the S1 subunit RBD to inhibit virus–cell receptor binding, whereas others bind to the S2 subunit to interrupt virus–cell fusion<sup><xref ref-type="bibr" rid="CR160">160</xref>
</sup>
. Regardless of their binding sites and mechanisms, these mAbs exhibit neutralizing activities and reduced viral titres <italic>in vitro</italic>
and/or in small animal models. Similarly, several mAbs targeting different epitopes on the S1 subunit RBD of MERS-CoV S have been developed<sup><xref ref-type="bibr" rid="CR94">94</xref>
,<xref ref-type="bibr" rid="CR95">95</xref>
,<xref ref-type="bibr" rid="CR96">96</xref>
,<xref ref-type="bibr" rid="CR97">97</xref>
,<xref ref-type="bibr" rid="CR100">100</xref>
</sup>
. These monoclonal antibodies bind to the RBD with 10-fold to >450-fold higher affinity than does human DPP4, resulting in broader and higher neutralizing activity <italic>in vitro</italic>
. Importantly, combination therapy with two or more synergistically acting humanized or human mAbs targeting non-cross-resistant epitopes or different regions of S may help to reduce the frequency with which viruses mutate to escape antibody-mediated neutralization<sup><xref ref-type="bibr" rid="CR94">94</xref>
</sup>
. Treatment with these mAbs showed protective effects in MERS-CoV-infected human DPP4-transgenic mice and mice transduced by adenoviral vectors expressing human DPP4 (Refs <xref ref-type="bibr" rid="CR100">100</xref>
,<xref ref-type="bibr" rid="CR161">161</xref>
,<xref ref-type="bibr" rid="CR162">162</xref>
). Their safety profiles and treatment effects in patients should be further evaluated.</p>
<p id="Par40">Antiviral peptides targeting different regions of S are another promising therapeutic strategy. The S2 subunits or stalk regions of both SARS-CoV and MERS-CoV S are class I viral fusion proteins that each contain an N-terminal fusion peptide, heptad repeat 1 (HR1) and HR2 domains, a transmembrane domain and a cytoplasmic domain<sup><xref ref-type="bibr" rid="CR92">92</xref>
</sup>
. Antiviral peptides analogous to the N terminus, pre-transmembrane domain or the loop region separating the HR1 and HR2 domains of SARS-CoV inhibited virus plaque formation by 40–80% at micromolar concentrations<sup><xref ref-type="bibr" rid="CR163">163</xref>
,<xref ref-type="bibr" rid="CR164">164</xref>
</sup>
. Similarly, antiviral peptides spanning the HR2 domain of MERS-CoV inhibit S-mediated cell–cell fusion and viral entry into cells <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR92">92</xref>
,<xref ref-type="bibr" rid="CR93">93</xref>
</sup>
. A peptide called HP2P-M2 that is derived from the HR2 domain, if administered intranasally before or after viral challenge, protected C57BL/6 mice and mice deficient for V(D)J recombination-activating protein 1 (RAG1) that were recently transduced by adenoviral vectors expressing human DPP4 from MERS-CoV infection with 10-fold to >1,000-fold reduction in viral titres in the lung; this protection was enhanced by combining this peptide with interferon beta<sup><xref ref-type="bibr" rid="CR99">99</xref>
</sup>
. Combining antiviral peptides targeting different regions of the S2 subunit may be synergistic <italic>in vitro</italic>
and overcome the theoretical risk of drug resistance<sup><xref ref-type="bibr" rid="CR165">165</xref>
</sup>
. Importantly, an analogous fusion inhibitor, enfuvirtide, which binds to glycoprotein 41 of HIV to block membrane fusion and HIV cell entry, has been successfully marketed for treatment of HIV-1 infection<sup><xref ref-type="bibr" rid="CR166">166</xref>
</sup>
. Primary resistance to enfuvirtide is rare and can be overcome by modifying the drug such that it contains secondary compensatory mutations<sup><xref ref-type="bibr" rid="CR167">167</xref>
,<xref ref-type="bibr" rid="CR168">168</xref>
</sup>
. This example of successful drug development includes measures to counteract drug resistance and therefore favours antiviral peptides over anti-CoV S siRNAs for further evaluation <italic>in vivo</italic>
; siRNAs have remained in preclinical development despite their reported antiviral activities <italic>in vitro</italic>
and in SARS-CoV-infected rhesus macaques owing to the lack of reliable drug delivery methods in humans<sup><xref ref-type="bibr" rid="CR169">169</xref>
,<xref ref-type="bibr" rid="CR170">170</xref>
,<xref ref-type="bibr" rid="CR171">171</xref>
,<xref ref-type="bibr" rid="CR172">172</xref>
</sup>
.</p>
<p id="Par41">Another class of anti-CoV agents that target S to inhibit CoV entry is the carbohydrate-binding agents. Griffithsin is an antiviral protein originally isolated from the red alga <italic>Griffithsia</italic>
spp.<sup><xref ref-type="bibr" rid="CR173">173</xref>
</sup>
. It binds specifically to oligosaccharides on viral surface glycoproteins such as S and HIV glycoprotein 120. It inhibits a broad range of CoVs, including SARS-CoV, HCoV-229E, HCoV-OC43 and HCoV-NL63 <italic>in vitro</italic>
and in SARS-CoV-infected mice<sup><xref ref-type="bibr" rid="CR173">173</xref>
,<xref ref-type="bibr" rid="CR174">174</xref>
</sup>
. The optimal delivery modes and safety profiles of these agents in humans should be further evaluated.</p>
<p id="Par42"><bold><italic>Viral envelope, membrane, nucleocapsid and accessory proteins.</italic>
</bold>
E, M and N and some of the accessory proteins are not only essential for virion assembly but may also have additional functions that suppress the host immune response to facilitate viral replication. For example, the accessory proteins 4a and 4b, and possibly also M and accessory protein 5 of MERS-CoV, exhibit interferon antagonist activities, and SARS-CoV N acts as a viral suppressor of RNA silencing and suppresses RNA interference triggered by either short hairpin RNAs or siRNAs<sup><xref ref-type="bibr" rid="CR175">175</xref>
,<xref ref-type="bibr" rid="CR176">176</xref>
,<xref ref-type="bibr" rid="CR177">177</xref>
,<xref ref-type="bibr" rid="CR178">178</xref>
</sup>
(<xref rid="Tab2" ref-type="table">Table 2</xref>
). siRNAs targeting E, M, N, ORF3a, ORF7a or ORF7b of SARS-CoV inhibited viral replication <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR179">179</xref>
,<xref ref-type="bibr" rid="CR180">180</xref>
</sup>
. However, similar to anti-CoV S siRNAs, none of these siRNAs is ready for human use until better delivery methods become available.</p>
<p id="Par43">Alternatively, an increasing number of agents that target specific binding sites or functions of these proteins are being generated through crystallography and functional assays. Examples include the <xref rid="Glos5" ref-type="list">viroporin</xref>
inhibitor hexamethylene amiloride, which reduces the ion channel activity of E in SARS-CoV and HCoV-229E, and PJ34, which binds to a distinct ribonucleotide-binding pocket at the N-terminal domain of N in HCoV-OC43 (Refs <xref ref-type="bibr" rid="CR181">181</xref>
,<xref ref-type="bibr" rid="CR182">182</xref>
,<xref ref-type="bibr" rid="CR183">183</xref>
). However, these agents are likely to be narrow-spectrum as the binding sites and functions of these proteins are unique to individual CoVs.</p>
<p id="Par44">Novel lipophilic thiazolidine derivatives, such as LJ001 and JL103, are membrane-binding photosensitizers that produce singlet oxygen molecules to induce changes in the properties of lipid membranes and prevent fusion between viral and target cell membranes. They exhibit broad-spectrum activities against numerous enveloped viruses and may be active against CoVs<sup><xref ref-type="bibr" rid="CR184">184</xref>
,<xref ref-type="bibr" rid="CR185">185</xref>
,<xref ref-type="bibr" rid="CR186">186</xref>
,<xref ref-type="bibr" rid="CR187">187</xref>
</sup>
.</p>
</sec>
<sec id="Sec5"><title>Host-based anti-CoV treatment options</title>
<p id="Par45"><bold><italic>Broad-spectrum host innate immune response.</italic>
</bold>
The host innate interferon response is crucial for the control of viral replication after infection<sup><xref ref-type="bibr" rid="CR188">188</xref>
</sup>
. Although CoVs are able to suppress the interferon response for immune evasion, they remain susceptible to interferon treatment <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR189">189</xref>
,<xref ref-type="bibr" rid="CR190">190</xref>
</sup>
. The interferon response can be augmented by the administration of recombinant interferons or interferon inducers (<xref rid="Tab3" ref-type="table">Table 3</xref>
). Recombinant interferon alfa and interferon beta inhibit the replication of both SARS-CoV and MERS-CoV <italic>in vitro</italic>
and in animal models<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR99">99</xref>
,<xref ref-type="bibr" rid="CR116">116</xref>
,<xref ref-type="bibr" rid="CR121">121</xref>
,<xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR148">148</xref>
,<xref ref-type="bibr" rid="CR191">191</xref>
,<xref ref-type="bibr" rid="CR192">192</xref>
</sup>
. Various combinations of interferon alfa or interferon beta with other antivirals such as ribavirin and/or lopinavir–ritonavir have been used to treat patients with SARS or MERS. Overall, combination treatments consisting of interferons and ribavirin did not consistently improve outcomes<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
</sup>
. The apparent discrepancy between <italic>in vitro</italic>
findings and <italic>in vivo</italic>
outcomes may be related to the high EC<sub>50</sub>
/C<sub>max</sub>
ratios of these drugs and the delay between symptom onset and drug administration<sup><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR121">121</xref>
,<xref ref-type="bibr" rid="CR122">122</xref>
</sup>
. This delay is especially relevant for MERS patients, as they have a much shorter median time interval between symptom onset and death than do SARS patients<sup><xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR58">58</xref>
</sup>
. The use of recombinant interferon beta-1b, which has the lowest EC<sub>50</sub>
/C<sub>max</sub>
ratio against MERS-CoV among tested preparations of recombinant interferons, should be evaluated in combination with other effective antivirals in clinical trials at early stages of the infection<sup><xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
</sup>
.<table-wrap id="Tab3"><label>Table 3</label>
<caption><title>Representative host-based treatment strategies for CoV infections</title>
<p><xref rid="MOESM10" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Targeted host factors</th>
<th>Examples</th>
<th>Mechanism of action</th>
<th>Status</th>
<th>Comments</th>
<th>Refs</th>
</tr>
</thead>
<tbody><tr><td align="center" colspan="6"><bold><italic>Broad-spectrum host innate immune response</italic>
</bold>
</td>
</tr>
<tr><td rowspan="3">Interferon response</td>
<td>Recombinant interferons (interferon alfa, interferon beta, interferon gamma)</td>
<td>Exogenous interferons</td>
<td>Marketed</td>
<td><p>• Broad spectrum against many CoVs and other viruses</p>
<p>• Recombinant interferon beta was more potent than interferon alfa for SARS-CoV and MERS-CoV <italic>in vitro</italic>
</p>
<p>• Interferon alfa reduced viral titres in lungs of SARS-CoV-infected mice and cynomolgus macaques</p>
<p>• Intranasal interferon beta administered before or after MERS-CoV challenge reduced viral titres in the lungs of <italic>Ad5-hDPP4</italic>
C57BL/6 and <italic>Rag1</italic>
<sup><italic>−/−</italic>
</sup>
mice by 10–100 fold</p>
<p>• Subcutaneous interferon beta-1b improved outcomes of MERS-CoV-infected common marmosets</p>
<p>• Benefits for SARS patients are uncertain</p>
<p>• Benefits of interferon alfa-2a, interferon alfa-2b and interferon beta-1a for MERS patients are uncertain</p>
</td>
<td><xref ref-type="bibr" rid="CR8">8</xref>
,<xref ref-type="bibr" rid="CR9">9</xref>
,<xref ref-type="bibr" rid="CR74">74</xref>
,<xref ref-type="bibr" rid="CR86">86</xref>
,<xref ref-type="bibr" rid="CR87">87</xref>
,<xref ref-type="bibr" rid="CR89">89</xref>
,<xref ref-type="bibr" rid="CR99">99</xref>
,<xref ref-type="bibr" rid="CR116">116</xref>
,<xref ref-type="bibr" rid="CR121">121</xref>
,<xref ref-type="bibr" rid="CR122">122</xref>
,<xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR148">148</xref>
,<xref ref-type="bibr" rid="CR191">191</xref>
,<xref ref-type="bibr" rid="CR192">192</xref>
,<xref ref-type="bibr" rid="CR215">215</xref>
</td>
</tr>
<tr><td>Poly(I:C)</td>
<td>Induces interferon production</td>
<td>Phase II clinical trials</td>
<td><p>• Reduced MERS-CoV load in <italic>Ad5-hDPP4</italic>
BALB/c mice</p>
<p>• Used in Phase II clinical trials of patients with malignant gliomas</p>
</td>
<td><xref ref-type="bibr" rid="CR157">157</xref>
,<xref ref-type="bibr" rid="CR193">193</xref>
,<xref ref-type="bibr" rid="CR194">194</xref>
</td>
</tr>
<tr><td>Nitazoxanide</td>
<td>A thiazolide that induces the host innate immune response by potentiation of interferon alfa and interferon beta production by fibroblasts and activation of PKR</td>
<td>Marketed</td>
<td><p>• Broad spectrum: canine CoV, IAV, IBV, RSV, PIF, Sendai virus, rhinovirus, norovirus, rotavirus, Dengue virus, JEV, YFV, HBV, HCV and HIV</p>
<p>• Used in patients with parasitic infections and in Phase II and III clinical trials of HCV infection and influenza</p>
<p>• Activity against human-pathogenic CoVs has yet to be determined</p>
</td>
<td><xref ref-type="bibr" rid="CR195">195</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Other host signalling pathways involved in viral replication</italic>
</bold>
</td>
</tr>
<tr><td>Cyclophilins</td>
<td>Cyclosporine, alisporivir</td>
<td>Cyclophilin inhibitor that could modulate the interaction of cyclophilins with SARS-CoV nsp1 and the calcineurin–NFAT pathway</td>
<td>Marketed</td>
<td><p>• Broad spectrum: CoVs (SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, and animal CoVs), HIV, HCV, HPV, vaccinia virus and VSV</p>
<p>• Alisporivir does not have the immunosuppressive effects of cyclosporine and may therefore be a more suitable antiviral candidate</p>
</td>
<td><xref ref-type="bibr" rid="CR118">118</xref>
,<xref ref-type="bibr" rid="CR119">119</xref>
,<xref ref-type="bibr" rid="CR120">120</xref>
,<xref ref-type="bibr" rid="CR200">200</xref>
</td>
</tr>
<tr><td>Kinase signalling pathways</td>
<td>Trametinib, selumetinib, everolimus, rapamycin, dasatinib and imatinib</td>
<td>Kinase signalling inhibitors that block the ABL1, ERK–MAPK and/or PI3K–AKT–mTOR pathways, which may block early viral entry and/or post-entry events</td>
<td>Marketed</td>
<td><p>• Active against SARS-CoV and MERS-CoV</p>
<p>• May be associated with immunopathology</p>
</td>
<td><xref ref-type="bibr" rid="CR124">124</xref>
,<xref ref-type="bibr" rid="CR125">125</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Host receptors utilized by CoVs for viral entry</italic>
</bold>
</td>
</tr>
<tr><td>ACE2</td>
<td>P4 and P5 peptides and NAAE</td>
<td>ACE2-derived peptides or small molecules targeting ACE2 that block SARS-CoV S-mediated cell fusion</td>
<td>Marketed</td>
<td><p>• Narrow spectrum: SARS-CoV</p>
<p>• May affect important biological functions such as blood pressure regulation</p>
</td>
<td><xref ref-type="bibr" rid="CR202">202</xref>
,<xref ref-type="bibr" rid="CR203">203</xref>
</td>
</tr>
<tr><td>DPP4</td>
<td>Anti-DPP4 mAb clones 2F9 and YS110</td>
<td>Anti-DPP4 mAbs that block MERS-CoV S-mediated cell fusion</td>
<td>Phase I clinical trial</td>
<td><p>• Narrow spectrum: MERS-CoV</p>
<p>• May affect important biological functions such as glucose metabolism and immunological responses</p>
<p>• mAb clone YS110 was used in a Phase I clinical trial of patients with advanced malignancies</p>
</td>
<td><xref ref-type="bibr" rid="CR102">102</xref>
,<xref ref-type="bibr" rid="CR201">201</xref>
,<xref ref-type="bibr" rid="CR227">227</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Host proteases utilized by CoVs for viral entry</italic>
</bold>
</td>
</tr>
<tr><td>Endosomal protease (for example, cathepsins)</td>
<td>E64D, K11777 and the small molecule 5705213</td>
<td>Cathepsin inhibitors that block endosomal protease-mediated cleavage and the endosomal entry pathway</td>
<td>Preclinical</td>
<td><p>• Broad spectrum: CoVs (SARS-CoV and MERS-CoV), filoviruses (Ebola virus) and paramyxoviruses (Hendra and Nipah viruses)</p>
<p>• Combination with TMPRSS2 inhibitors necessary for complete inhibition of MERS-CoV <italic>in vitro</italic>
</p>
</td>
<td><xref ref-type="bibr" rid="CR111">111</xref>
,<xref ref-type="bibr" rid="CR124">124</xref>
,<xref ref-type="bibr" rid="CR127">127</xref>
,<xref ref-type="bibr" rid="CR283">283</xref>
</td>
</tr>
<tr><td>Surface protease (for example, TMPRSS2)</td>
<td>Camostat mesylate</td>
<td>TMPRSS2 inhibitor that blocks the TMPRSS2-mediated cell surface entry pathway</td>
<td>Marketed</td>
<td><p>• Broad spectrum: CoVs (SARS-CoV, MERS-CoV and HCoV-229E), IAV and PIF</p>
<p>• Combination with cathepsin inhibitors is necessary for complete inhibition of MERS-CoV <italic>in vitro</italic>
</p>
<p>• Used to treat patients with chronic pancreatitis</p>
</td>
<td><xref ref-type="bibr" rid="CR109">109</xref>
,<xref ref-type="bibr" rid="CR111">111</xref>
,<xref ref-type="bibr" rid="CR207">207</xref>
,<xref ref-type="bibr" rid="CR208">208</xref>
,<xref ref-type="bibr" rid="CR284">284</xref>
,<xref ref-type="bibr" rid="CR285">285</xref>
,<xref ref-type="bibr" rid="CR286">286</xref>
</td>
</tr>
<tr><td>Other host proteases (for example, furin)</td>
<td>dec-RVKR-CMK</td>
<td>Furin inhibitor that blocks furin-mediated cleavage of S</td>
<td>Preclinical</td>
<td>Active against MERS-CoV and may be active against other CoVs that utilize furin for S cleavage</td>
<td><xref ref-type="bibr" rid="CR110">110</xref>
</td>
</tr>
<tr><td align="center" colspan="6"><bold><italic>Endocytosis</italic>
</bold>
</td>
</tr>
<tr><td>Clathrin-mediated endocytosis</td>
<td>Chlorpromazine</td>
<td>An antipsychotic that also affects the assembly of clathrin-coated pits at the plasma membrane</td>
<td>Marketed</td>
<td><p>• Broad spectrum: SARS-CoV, MERS-CoV, HCV and alphaviruses</p>
<p>• Clinical benefit uncertain owing to a high EC<sub>50</sub>
/C<sub>max</sub>
ratio at the usual therapeutic dosages</p>
</td>
<td><xref ref-type="bibr" rid="CR123">123</xref>
</td>
</tr>
<tr><td>Clathrin-mediated endocytosis</td>
<td>Ouabain and bufalin</td>
<td>ATP1A1-binding cardiotonic steroids that inhibit clathrin-mediated endocytosis</td>
<td>Marketed</td>
<td><p>• Active against MERS-CoV at nanomolar concentrations <italic>in vitro</italic>
</p>
<p>• May have risk of toxicity</p>
</td>
<td><xref ref-type="bibr" rid="CR209">209</xref>
</td>
</tr>
<tr><td>Endosomal acidification</td>
<td>Chloroquine</td>
<td>An antimalarial that sequesters protons in lysosomes to increase the intracellular pH</td>
<td>Marketed</td>
<td><p>• Broad spectrum: CoVs (SARS-CoV, MERS-CoV, HCoV-229E and HCoV-OC43), HIV, flaviviruses and Ebola, Hendra and Nipah viruses <italic>in vitro</italic>
</p>
<p>• Not active against SARS-CoV-infected mice</p>
</td>
<td><xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR210">210</xref>
,<xref ref-type="bibr" rid="CR211">211</xref>
,<xref ref-type="bibr" rid="CR212">212</xref>
,<xref ref-type="bibr" rid="CR213">213</xref>
,<xref ref-type="bibr" rid="CR214">214</xref>
,<xref ref-type="bibr" rid="CR215">215</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>ACE2, angiotensin-converting enzyme 2; Ad5-hDPP4, adenovirus type 5 expressing human dipeptidyl peptidase 4; ATP1A1, ATPase subunit α1; C<sub>max</sub>
, peak serum concentration; CoV, coronavirus; dec-RVKR-CMK, decanoyl-Arg-Val-Lys-Arg-chloromethylketone; DPP4; dipeptidyl peptidase 4; EC<sub>50</sub>
, half-maximal effective concentration; ERK, extracellular signal-regulated kinase; HBV, hepatitis B virus; HCoV, human coronavirus; HCV, hepatitis C virus; HPV, human papillomavirus; IAV, influenza A virus; IBV, influenza B virus; JEV, Japanese encephalitis virus; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MERS, Middle East respiratory syndrome; mTOR, mammalian target of rapamycin; NAAE, N-(2-aminoethyl)-1-aziridine-ethanamine; NFAT, nuclear factor of activated T cells; nsp1, non-structural protein 1; PI3K, phosphoinositide 3-kinase; PIF, parainfluenza virus; PKR, protein kinase R; poly(I:C), polyinosinic:polycytidylic acid; RSV, respiratory syncytial virus; S, spike glycoprotein; SARS, severe acute respiratory syndrome; TMPRSS2, transmembrane protease serine 2; VSV, vesicular stomatitis virus; YFV, yellow fever virus.</p>
</table-wrap-foot>
</table-wrap>
</p>
<p id="Par46">Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic analogue of dsRNA that strongly induces type I interferons. It substantially reduced the MERS-CoV load in BALB/c mice that were transduced by adenoviral vectors expressing human DPP4 shortly before poly(I:C) administration, although its effects in standard cell culture protection assays are not published<sup><xref ref-type="bibr" rid="CR157">157</xref>
</sup>
. Intramuscular injection of poly(I:C) stabilized with poly-L-lysine and carboxymethylcellulose seemed to be well tolerated by patients with malignant gliomas in Phase II clinical trials<sup><xref ref-type="bibr" rid="CR193">193</xref>
,<xref ref-type="bibr" rid="CR194">194</xref>
</sup>
. Nitazoxanide is another potent type I interferon inducer that has been used in humans for parasitic infections<sup><xref ref-type="bibr" rid="CR195">195</xref>
</sup>
. It is a synthetic nitrothiazolyl–salicylamide derivative that exhibits broad-spectrum antiviral activities against both RNA and DNA viruses including canine CoV, influenza viruses, HBV, HCV, HIV, rotavirus, norovirus and flaviviruses<sup><xref ref-type="bibr" rid="CR195">195</xref>
</sup>
. It has been evaluated in Phase II and Phase III clinical trials for the treatment of HCV infection and influenza and has a good safety profile<sup><xref ref-type="bibr" rid="CR195">195</xref>
,<xref ref-type="bibr" rid="CR196">196</xref>
,<xref ref-type="bibr" rid="CR197">197</xref>
</sup>
. Other innate immunomodulators that have anti-SARS-CoV effects in animal models include the antimicrobial peptide rhesus θ-defensin 1 and <xref rid="Glos6" ref-type="list">protein cage nanoparticles</xref>
that elicit a host immune response in inducible bronchus-associated lymphoid tissue<sup><xref ref-type="bibr" rid="CR198">198</xref>
,<xref ref-type="bibr" rid="CR199">199</xref>
</sup>
. The combined use of interferon inducers and innate immunomodulators with effective antiviral agents may be synergistic and should be evaluated in animal models.</p>
<p id="Par47"><bold><italic>Other host signalling pathways involved in viral replication.</italic>
</bold>
In addition to direct potentiation of the interferon response, other cell signalling pathways have been identified as potential anti-CoV treatment targets (<xref rid="Tab3" ref-type="table">Table 3</xref>
). Cyclophilins interact with SARS-CoV nsp1 to modulate the calcineurin pathway, which is important in the T cell-mediated adaptive immune response<sup><xref ref-type="bibr" rid="CR120">120</xref>
</sup>
. The calcineurin inhibitor cyclosporine inhibits a broad range of CoVs <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR118">118</xref>
,<xref ref-type="bibr" rid="CR119">119</xref>
,<xref ref-type="bibr" rid="CR120">120</xref>
</sup>
. However, its clinical application is limited by its immunosuppressive effects and high EC<sub>50</sub>
/C<sub>max</sub>
ratio at standard therapeutic dosages. The antiviral activities of newer, non-immunosuppressive calcineurin inhibitors, which are active against HCoV-NL63, should be evaluated for SARS-CoV and MERS-CoV<sup><xref ref-type="bibr" rid="CR200">200</xref>
</sup>
. Similarly, agents that modulate other cellular signalling pathways, such as kinase signalling pathway inhibitors, also exhibit anti-CoV activities and are commercially available<sup><xref ref-type="bibr" rid="CR124">124</xref>
,<xref ref-type="bibr" rid="CR125">125</xref>
</sup>
. However, their toxicities may limit their use in patients with severe CoV infections.</p>
<p id="Par48"><bold><italic>Host factors utilized by CoVs for viral replication.</italic>
</bold>
CoVs utilize specific host factors for virus entry and replication (<xref rid="Fig2" ref-type="fig">Fig. 2</xref>
). The host receptor can be targeted by specific monoclonal or polyclonal antibodies, peptides or functional inhibitors (<xref rid="Tab3" ref-type="table">Table 3</xref>
). For example, anti-DPP4 mAbs inhibit MERS-CoV cell entry <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR201">201</xref>
</sup>
. YS110 is a recombinant humanized IgG1 anti-DPP4 mAb that seems to be well tolerated in patients with advanced solid tumours<sup><xref ref-type="bibr" rid="CR201">201</xref>
</sup>
. For the treatment of SARS-CoV, small-molecule entry inhibitors such as N-(2-aminoethyl)-1-aziridine-ethanamine (NAAE) inhibit the catalytic activity of ACE2 and SARS-CoV S-mediated cell–cell fusion <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR202">202</xref>
</sup>
. Synthetic peptides analogous to critical segments of ACE2 also have anti-SARS-CoV activity at micromolar concentrations <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR203">203</xref>
</sup>
. However, none of these receptor-directed compounds has yet been tested in patients with CoV infections. Their anti-CoV activity is likely to be narrow-spectrum, as different CoVs utilize different host cell receptors. Furthermore, the risks of immunopathology must be assessed, especially given the multiple essential biological and immunological functions of these receptors.</p>
<p id="Par49">The entry of CoVs into host cells via the endosomal and/or cell surface pathways is facilitated by host proteases that cleave and activate S. Cathepsins are cysteine proteases that are involved in the endosomal pathway and can be inhibited by cathepsin inhibitors such as K11777 and its related vinylsulfone analogues<sup><xref ref-type="bibr" rid="CR111">111</xref>
</sup>
. These compounds seem to be safe and effective against various parasitic infections in animal models, and have broad-spectrum activities against enveloped RNA viruses such as CoVs (SARS-CoV, MERS-CoV, HCoV-229E and HCoV-NL63), filoviruses (Ebola and Marburg viruses) and paramyxoviruses<sup><xref ref-type="bibr" rid="CR111">111</xref>
,<xref ref-type="bibr" rid="CR204">204</xref>
,<xref ref-type="bibr" rid="CR205">205</xref>
,<xref ref-type="bibr" rid="CR206">206</xref>
</sup>
. TMPRSS2 is a serine protease that mediates the cell surface entry pathway; camostat mesylate is a synthetic low-molecular-weight serine protease inhibitor that has been used to treat chronic pancreatitis in humans with minimal side effects<sup><xref ref-type="bibr" rid="CR207">207</xref>
,<xref ref-type="bibr" rid="CR208">208</xref>
</sup>
. This molecule inhibits SARS-CoV and MERS-CoV <italic>in vitro</italic>
and improves survival of SARS-CoV-infected mice<sup><xref ref-type="bibr" rid="CR109">109</xref>
,<xref ref-type="bibr" rid="CR111">111</xref>
</sup>
. Furin, another ubiquitously expressed host protease, is also important in MERS-CoV S-mediated entry. Blocking furin with decanoyl-Arg-Val-Lys-Arg-chloromethylketone inhibits MERS-CoV entry and cell–cell fusion <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR110">110</xref>
</sup>
.</p>
<p id="Par50">Another group of candidate anti-CoV drugs target the endocytosis of CoV during cell entry. Chlorpromazine is an antipsychotic drug used in the treatment of schizophrenia that also affects the assembly of clathrin-coated pits at the plasma membrane. It is active against HCV, alphaviruses and numerous CoVs, including SARS-CoV and MERS-CoV, <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR123">123</xref>
</sup>
. Cardiotonic steroids that bind sodium/potassium-transporting ATPase subunit α1, such as ouabain and bufalin, also inhibit clathrin-mediated endocytosis of MERS-CoV at nanomolar concentrations<sup><xref ref-type="bibr" rid="CR209">209</xref>
</sup>
. However, the use of these clathrin-mediated endocytosis inhibitors in patients with CoV infections is limited by either very high EC<sub>50</sub>
/C<sub>max</sub>
ratios or toxicity. Alternatively, endocytosis can also be suppressed by a high pH. Chloroquine is an anti-malarial drug that sequesters protons into lysosomes to increase the intracellular pH. It has broad-spectrum antiviral activities against numerous CoVs (SARS-CoV, MERS-CoV, HCoV-229E and HCoV-OC43) and other RNA viruses <italic>in vitro</italic>
<sup><xref ref-type="bibr" rid="CR123">123</xref>
,<xref ref-type="bibr" rid="CR210">210</xref>
,<xref ref-type="bibr" rid="CR211">211</xref>
,<xref ref-type="bibr" rid="CR212">212</xref>
,<xref ref-type="bibr" rid="CR213">213</xref>
,<xref ref-type="bibr" rid="CR214">214</xref>
</sup>
. However, it did not substantially reduce viral replication in SARS-CoV-infected mice, possibly because the cell surface pathway was not simultaneously blocked<sup><xref ref-type="bibr" rid="CR215">215</xref>
</sup>
. The anti-CoV effects, pharmacokinetic and pharmacodynamic profiles and toxicity of the combinations of different protease and endocytosis inhibitors that target these different cell entry pathways should be further evaluated <italic>in vivo</italic>
.</p>
</sec>
<sec id="Sec6"><title>Development of MERS-CoV vaccines</title>
<p id="Par51">Rapid diagnostics and effective vaccines are often complementary to antiviral treatment in the control of epidemics caused by emerging viruses (<xref rid="Sec7" ref-type="sec">Box 1</xref>
). Although there has not been any new human SARS case for over 10 years, sporadic cases and clusters of MERS continue to occur in the Middle East owing to the persistence of zoonotic sources in endemic areas, and these cases spread to other regions. Effective MERS-CoV vaccines are essential for interrupting the chain of transmission from animal reservoirs and infected humans to susceptible hosts. Live-attenuated vaccines, which have been previously evaluated in animal models for SARS, might be associated with disseminated infection in immunocompromised patients. Inactivated vaccines might be associated with immunopathology during animal challenge. These are unfavourable approaches for MERS vaccine development because a substantial proportion of patients with severe MERS have comorbidities or systemic immunocompromising conditions. Other vaccination strategies for MERS that use DNA plasmids, viral vectors, nanoparticles, virus-like particles and recombinant protein subunits are in development and some have been evaluated in animal models<sup><xref ref-type="bibr" rid="CR157">157</xref>
,<xref ref-type="bibr" rid="CR216">216</xref>
,<xref ref-type="bibr" rid="CR217">217</xref>
,<xref ref-type="bibr" rid="CR218">218</xref>
,<xref ref-type="bibr" rid="CR219">219</xref>
,<xref ref-type="bibr" rid="CR220">220</xref>
,<xref ref-type="bibr" rid="CR221">221</xref>
,<xref ref-type="bibr" rid="CR222">222</xref>
,<xref ref-type="bibr" rid="CR223">223</xref>
,<xref ref-type="bibr" rid="CR224">224</xref>
,<xref ref-type="bibr" rid="CR225">225</xref>
,<xref ref-type="bibr" rid="CR226">226</xref>
,<xref ref-type="bibr" rid="CR227">227</xref>
,<xref ref-type="bibr" rid="CR228">228</xref>
,<xref ref-type="bibr" rid="CR229">229</xref>
,<xref ref-type="bibr" rid="CR230">230</xref>
,<xref ref-type="bibr" rid="CR231">231</xref>
,<xref ref-type="bibr" rid="CR232">232</xref>
,<xref ref-type="bibr" rid="CR233">233</xref>
</sup>
(<xref rid="Tab4" ref-type="table">Table 4</xref>
). The availability of a safe and effective MERS-CoV vaccine for dromedary camels and non-immune individuals at high risk of camel contact in endemic regions such as the Middle East and the greater Horn of Africa would be an important measure for controlling the ongoing epidemic.<table-wrap id="Tab4"><label>Table 4</label>
<caption><title>MERS-CoV candidate vaccines in development</title>
<p><xref rid="MOESM11" ref-type="media">PowerPoint slide</xref>
</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th>Vaccine type</th>
<th>Examples</th>
<th>Vaccine design strategy</th>
<th>Comments</th>
<th>Refs</th>
</tr>
</thead>
<tbody><tr><td>Live attenuated virus</td>
<td>rMERS-CoV-ΔE</td>
<td>Deletion of the gene encoding MERS-CoV E rendered the mutant virus replication-competent and propagation-defective</td>
<td><p>• Attenuated SARS-CoV-ΔE mutant virus induced protection in mice and hamsters</p>
<p>• No animal data are available for a rMERS-CoV-ΔE-based vaccine yet</p>
<p>• Risk of disseminated infection in immunocompromised patients</p>
</td>
<td><xref ref-type="bibr" rid="CR218">218</xref>
,<xref ref-type="bibr" rid="CR287">287</xref>
,<xref ref-type="bibr" rid="CR288">288</xref>
,<xref ref-type="bibr" rid="CR289">289</xref>
,<xref ref-type="bibr" rid="CR290">290</xref>
,<xref ref-type="bibr" rid="CR291">291</xref>
,<xref ref-type="bibr" rid="CR292">292</xref>
,<xref ref-type="bibr" rid="CR293">293</xref>
,<xref ref-type="bibr" rid="CR294">294</xref>
,<xref ref-type="bibr" rid="CR295">295</xref>
</td>
</tr>
<tr><td>DNA plasmid</td>
<td>MERS-CoV S DNA</td>
<td>DNA plasmids that encode full-length MERS-CoV S</td>
<td><p>• BALB/cJ mice vaccinated with MERS-CoV S-encoding DNA developed neutralizing anti-MERS-CoV antibodies</p>
<p>• The neutralizing antibody titre was boosted 10-fold after vaccination with S1 protein</p>
<p>• Rhesus macaques vaccinated sequentially with MERS-CoV S-encoding DNA and S1 protein had reduced CT scan abnormalities</p>
</td>
<td><xref ref-type="bibr" rid="CR219">219</xref>
</td>
</tr>
<tr><td>Viral vectors</td>
<td>MVA-MERS-S, Ad5-MERS-S, Ad5-MERS-S1, Ad5-S and Ad41-S</td>
<td>Viral vectors (MVA or Ad) that express full-length MERS-CoV S or the S1 subunit of MERS-CoV S</td>
<td><p>• Both MVA and Ad vector-based vaccines induced neutralising anti-MERS-CoV antibodies in BALB/c mice</p>
<p>• A MVA-MERS-S vaccine conferred mucosal immunity and induced serum neutralizing anti-MERS-CoV antibodies in dromedary camels</p>
<p>• Mucosal (intragastric) administration of Ad5-S or Ad41-S vaccines induced the production of antigen-specific IgG and neutralizing antibodies, but not antigen-specific T cell responses, in BALB/c mice</p>
<p>• Systemic (intramuscular) administration of Ad5-S or Ad41-S vaccines induced antigen-specific neutralizing IgG antibodies, as well as T cell responses in splenic and pulmonary lymphocytes</p>
<p>• Increased immunopathology with severe hepatitis in SARS-CoV-infected ferrets that were previously vaccinated with an MVA-based vaccine expressing full-length SARS-CoV S</p>
</td>
<td><xref ref-type="bibr" rid="CR220">220</xref>
,<xref ref-type="bibr" rid="CR221">221</xref>
,<xref ref-type="bibr" rid="CR222">222</xref>
,<xref ref-type="bibr" rid="CR223">223</xref>
,<xref ref-type="bibr" rid="CR224">224</xref>
,<xref ref-type="bibr" rid="CR298">298</xref>
</td>
</tr>
<tr><td>Nanoparticles</td>
<td>MERS-CoV S-containing nanoparticles</td>
<td>Purified MERS-CoV S-containing nanoparticles produced in insect (Sf9) cells that were infected with specific recombinant baculovirus containing the gene encoding MERS-CoV S</td>
<td><p>• BALB/c mice vaccinated with MERS-CoV or SARS-CoV S-containing nanoparticles developed neutralizing antibodies specific to the viral S</p>
<p>• Adjuvant matrix M1 or alum is required to elicit an optimal neutralizing antibody response</p>
</td>
<td><xref ref-type="bibr" rid="CR225">225</xref>
</td>
</tr>
<tr><td>Virus-like particles</td>
<td>VRP-S</td>
<td>VEE virus-like replicon particles containing MERS-CoV S</td>
<td>Vaccination of BALB/c mice transduced with Ad5-hDPP4 with VRP-S reduced viral titres in lungs to nearly undetectable levels by day 1 after inoculation with MERS-CoV</td>
<td><xref ref-type="bibr" rid="CR157">157</xref>
</td>
</tr>
<tr><td>Recombinant protein subunits</td>
<td>S(RBD)-Fc, S1(358–588)-Fc, S(377–588)-Fc and rRBD</td>
<td>Full-length MERS-CoV S or the RBD subunit of MERS-CoV S</td>
<td><p>• Vaccinated BALB/c mice and/or rabbits developed neutralizing antibodies</p>
<p>• Protective effects may be enhanced by combination with different adjuvants</p>
<p>• Non-neutralizing epitopes in full-length S-based vaccines may induce antibody-mediated disease enhancement</p>
</td>
<td><xref ref-type="bibr" rid="CR226">226</xref>
,<xref ref-type="bibr" rid="CR227">227</xref>
,<xref ref-type="bibr" rid="CR228">228</xref>
,<xref ref-type="bibr" rid="CR229">229</xref>
,<xref ref-type="bibr" rid="CR230">230</xref>
,<xref ref-type="bibr" rid="CR231">231</xref>
,<xref ref-type="bibr" rid="CR232">232</xref>
,<xref ref-type="bibr" rid="CR233">233</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot><p>Ad, adenovirus; CoV, coronavirus; CT, computerized tomography; E, envelope protein; hDPP4, human dipeptidyl peptidase 4; IgG, immunoglobulin G; MERS, Middle East respiratory syndrome; MVA, modified vaccinia virus Ankara; RBD, receptor-binding domain; rRBD, recombinant RBD; S, spike glycoprotein; SARS,severe acute respiratory syndrome; S(RBD)-Fc, RBD of S fused to the antibody crystallizable fragment; S1(358–588)-Fc, amino acid residues 358–588 of the S1 subunit of S fused to the antibody crystallizable fragment; VEE, Venezuelan equine encephalitis; VRP, virus replicon particle.</p>
</table-wrap-foot>
</table-wrap>
</p>
<sec id="Sec7"><boxed-text><label>Box 1: The complementary roles of novel rapid diagnostics and antiviral agents</label>
<p id="Par52">As demonstrated in the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) epidemics, rapid and accurate laboratory diagnosis is essential for the clinical management and epidemiological control of coronavirus (CoV) infections. Real-time reverse transcription (RT)-PCR assays, which can quantify viral loads, have facilitated studies on viral shedding patterns and optimization of treatment and infection control strategies. The peak viral load in SARS was found to occur at day 10 after symptom onset and helped to predict the timing of clinical deterioration and the need for intensive supportive care<sup><xref ref-type="bibr" rid="CR18">18</xref>
,<xref ref-type="bibr" rid="CR249">249</xref>
</sup>
. Point-of-care nucleic amplification tests such as RT-loop-mediated isothermal amplification and RT-isothermal recombinase polymerase amplification are suitable for field evaluation, especially in resource-limited areas<sup><xref ref-type="bibr" rid="CR250">250</xref>
,<xref ref-type="bibr" rid="CR251">251</xref>
</sup>
. Similarly, assays that detect abundantly expressed CoV antigens, such as the nucleocapsid protein, can be used for fast and high-throughput laboratory diagnosis without requiring biosafety level 3 containment<sup><xref ref-type="bibr" rid="CR252">252</xref>
,<xref ref-type="bibr" rid="CR253">253</xref>
</sup>
. The rapid availability of complete genome sequences of most human and animal CoVs has minimized the time required for the design of new RT-PCR assays, source identification and molecular surveillance for emerging CoVs<sup><xref ref-type="bibr" rid="CR254">254</xref>
</sup>
. This was well illustrated in the MERS epidemic, in which highly sensitive and specific RT-PCR assays targeting unique gene regions such as the region upstream of the envelope (E) gene (upE region) were quickly developed after the complete genome sequence of MERS-CoV strains isolated from humans became available<sup><xref ref-type="bibr" rid="CR255">255</xref>
,<xref ref-type="bibr" rid="CR256">256</xref>
</sup>
. Comparative genomic studies quickly identified bats and camels carrying CoVs that were highly similar to MERS-CoV strains isolated from humans, and these two animals were determined to be the likely CoV reservoirs<sup><xref ref-type="bibr" rid="CR40">40</xref>
,<xref ref-type="bibr" rid="CR42">42</xref>
,<xref ref-type="bibr" rid="CR43">43</xref>
,<xref ref-type="bibr" rid="CR44">44</xref>
,<xref ref-type="bibr" rid="CR46">46</xref>
,<xref ref-type="bibr" rid="CR91">91</xref>
</sup>
. Continuous surveillance and analysis of MERS-CoV genomes obtained from patients and animals in different areas in the Middle East are important for detecting mutations that may increase the ability of the virus to be efficiently transmitted from person to person<sup><xref ref-type="bibr" rid="CR71">71</xref>
</sup>
. Data analyses from the sequencing of small RNAs and the use of locked nucleic acid probes have allowed the development of new assays that target short but abundantly expressed gene regions from CoV genomes, such as the leader sequences<sup><xref ref-type="bibr" rid="CR257">257</xref>
</sup>
. The increasing number of complete CoV genomes and diagnostic gene targets has enabled the development of multiplex assays that simultaneously detect multiple CoVs or multiple gene targets of a particular CoV<sup><xref ref-type="bibr" rid="CR257">257</xref>
</sup>
. The increasing use of these multiplex assays in clinical laboratories worldwide will enhance our understanding of the changing epidemiology of CoV infections and enable the stratification of at-risk patients and contact groups for early treatment and prophylaxis.</p>
<p id="Par53">In addition to improving acute clinical diagnosis, diagnostic advances have facilitated other aspects of the control of CoV epidemics and anti-CoV drug development. The isolation of infectious virus particles from clinical specimens in cell culture has a limited role in the acute diagnosis of CoV infection, as most human-pathogenic CoVs are either difficult or dangerous to culture<sup><xref ref-type="bibr" rid="CR258">258</xref>
</sup>
. Nevertheless, recent advances have enhanced their use in CoV pathogenesis studies, which are important for identifying new treatment targets. The previously unculturable HCoV-HKU1 can now be isolated from primary differentiated human tracheal bronchial epithelial cells and human alveolar type II cells that are cultured at an air–liquid interface<sup><xref ref-type="bibr" rid="CR259">259</xref>
,<xref ref-type="bibr" rid="CR260">260</xref>
,<xref ref-type="bibr" rid="CR261">261</xref>
,<xref ref-type="bibr" rid="CR262">262</xref>
</sup>
. <italic>Ex vivo</italic>
organ culture enables the identification of important viral and host factors that are involved in the severe pulmonary and extrapulmonary manifestations of SARS and MERS<sup><xref ref-type="bibr" rid="CR263">263</xref>
,<xref ref-type="bibr" rid="CR264">264</xref>
,<xref ref-type="bibr" rid="CR265">265</xref>
,<xref ref-type="bibr" rid="CR266">266</xref>
,<xref ref-type="bibr" rid="CR267">267</xref>
</sup>
. The number of available human and animal cell lines from various organs is increasing, and these provide insights into tissue and species tropism<sup><xref ref-type="bibr" rid="CR258">258</xref>
,<xref ref-type="bibr" rid="CR268">268</xref>
,<xref ref-type="bibr" rid="CR269">269</xref>
</sup>
. Similarly, detection of specific anti-CoV antibodies in paired acute and convalescent sera samples are mainly useful for seroepidemiological studies and contact tracing, but not for acute diagnosis<sup><xref ref-type="bibr" rid="CR41">41</xref>
,<xref ref-type="bibr" rid="CR49">49</xref>
,<xref ref-type="bibr" rid="CR51">51</xref>
,<xref ref-type="bibr" rid="CR270">270</xref>
</sup>
. Novel assays such as the spike glycoprotein (S) pseudoparticle neutralization assay, which do not require biosafety level 3 containment, enable high-throughput antibody detection in large-scale seroepidemiological studies and outbreak investigations<sup><xref ref-type="bibr" rid="CR271">271</xref>
</sup>
.</p>
</boxed-text>
</sec>
</sec>
<sec id="Sec8"><title>Outlook and challenges</title>
<p id="Par54"><bold><italic>Animal models for testing anti-CoV drugs.</italic>
</bold>
Suitable animal models are especially important for testing anti-CoV drugs because most of these drugs have not been used in humans. In contrast to the limited number of animal models established for the mild infections caused by HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1, various small animal and non-human primate models have been evaluated for studies of the pathogenesis and treatment of SARS and MERS<sup><xref ref-type="bibr" rid="CR234">234</xref>
,<xref ref-type="bibr" rid="CR235">235</xref>
,<xref ref-type="bibr" rid="CR236">236</xref>
,<xref ref-type="bibr" rid="CR237">237</xref>
</sup>
. The identification of ACE2 and DPP4 as the functional receptors for SARS-CoV and MERS-CoV, respectively, was essential to the development of animal models that are representative of severe human disease<sup><xref ref-type="bibr" rid="CR101">101</xref>
,<xref ref-type="bibr" rid="CR102">102</xref>
</sup>
. A number of different non-human primates were found to be permissive to SARS-CoV, but none of them consistently reproduced characteristics of the severe human disease, and mortality was not observed<sup><xref ref-type="bibr" rid="CR237">237</xref>
</sup>
. These models were predominantly useful to fulfil <xref rid="Glos7" ref-type="list">Koch's postulates</xref>
<sup><xref ref-type="bibr" rid="CR238">238</xref>
</sup>
. Small animals — including young and aged BALB/c and C57BL/6 mice, knockout mice with deficiencies in T, B and/or NK cells, golden Syrian hamsters and ferrets — could be productively infected with SARS-CoV, but few of them developed clinically apparent disease<sup><xref ref-type="bibr" rid="CR237">237</xref>
</sup>
. The best available small animal models for SARS utilize transgenic mice that express human ACE2 and/or mouse-adapted SARS-CoV strains that are capable of causing lethal disease in mice<sup><xref ref-type="bibr" rid="CR239">239</xref>
,<xref ref-type="bibr" rid="CR240">240</xref>
,<xref ref-type="bibr" rid="CR241">241</xref>
</sup>
. The limited availability of these ACE2-transgenic mice and mouse-adapted virus strains remains a major obstacle to testing anti-SARS-CoV drugs.</p>
<p id="Par55">Similar to SARS, non-human primate models were also used to fulfil Koch's postulates and investigate the pathogenesis of MERS. Rhesus macaques developed only a mild, self-limiting disease and were not optimal for the evaluation of treatments for MERS<sup><xref ref-type="bibr" rid="CR148">148</xref>
,<xref ref-type="bibr" rid="CR242">242</xref>
,<xref ref-type="bibr" rid="CR243">243</xref>
</sup>
. By contrast, MERS-CoV-infected common marmosets developed a disseminated and fatal infection that closely resembled severe human disease<sup><xref ref-type="bibr" rid="CR128">128</xref>
,<xref ref-type="bibr" rid="CR244">244</xref>
</sup>
. However, the availability of common marmosets is limited and experiments on these small primates are technically demanding. Therefore, other small animal models for MERS were evaluated. Unlike with SARS-CoV, most small animals — including BALB/c mice, golden Syrian hamsters, ferrets and rabbits — were not susceptible to MERS-CoV infection<sup><xref ref-type="bibr" rid="CR245">245</xref>
,<xref ref-type="bibr" rid="CR246">246</xref>
,<xref ref-type="bibr" rid="CR247">247</xref>
</sup>
. Intranasal inoculation of adenoviral vectors expressing human DPP4 followed by MERS-CoV inoculation was a novel method that rapidly rendered mice susceptible to MERS-CoV infection, but the disease was relatively mild and confined to the respiratory tract<sup><xref ref-type="bibr" rid="CR157">157</xref>
</sup>
. Transgenic mice expressing human DPP4 develop severe pulmonary and disseminated infection and are currently the best available small animal model for MERS<sup><xref ref-type="bibr" rid="CR248">248</xref>
</sup>
. Potential anti-MERS-CoV treatment options identified in <italic>in vitro</italic>
antiviral assays should be further evaluated in these transgenic mice.</p>
<p id="Par56"><bold><italic>Generic challenges in the clinical development of novel anti-CoV drugs.</italic>
</bold>
There are a number of virological and patient-associated factors that pose major challenges in the clinical development of novel anti-CoV drugs. First, CoVs are one of the most diverse and rapidly mutating groups of viruses, and novel CoVs emerge repeatedly at unpredictable times. Therefore, most anti-CoV drugs that specifically target the replication apparatus of an existing CoV may not be effective against another novel CoV. This is especially applicable to viral enzyme inhibitors, mAbs and antiviral peptides that target S, as well as agents that target the host cell receptor. Second, there are a limited number of animal models available for infections caused by HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1. Even for SARS and MERS, experiments using suitable animal models such as mice with transgenes encoding ACE2 or DPP4, and non-human primates, are only available in a few designated research biosafety level 3 laboratories, and these experiments are technically demanding. Last and most important, the mild clinical severity of infections caused by HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1, together with the absence of new SARS cases, have made recruitment of patients into clinical trials difficult and reduced the incentives for pharmaceutical companies to develop specific antiviral drugs for these CoV infections. The continuing threat of MERS-CoV to global health security 3 years after its first discovery presents a golden opportunity to tackle current obstacles in the development of new anti-CoV drugs. It is prudent that a well-organized, multidisciplinary, international collaborative network consisting of clinicians, virologists and drug developers, coupled to political commitment, is formed to carry out clinical trials using anti-CoV drugs that have already been shown to be safe and effective <italic>in vitro</italic>
and/or in animal models.</p>
<p id="Par57"><bold><italic>Prioritization of virus-based and host-based treatment options for clinical development.</italic>
</bold>
Despite the report of a large number of virus-based and host-based treatment options with potent <italic>in vitro</italic>
activities for SARS and MERS, only a few are likely to fulfil their potential in the clinical setting in the foreseeable future. Most drugs have one or more major limitations that prevent them from proceeding beyond the <italic>in vitro</italic>
stage. First, many drugs have high EC<sub>50</sub>
/C<sub>max</sub>
ratios at clinically relevant dosages. Examples of such drugs include cyclosporine, chlorpromazine and interferon alfa. Second, some have severe side effects or cause immunosuppression. For example, the use of high-dose ribavirin may be associated with haemolytic anaemia, neutropenia, teratogenicity and cardiorespiratory distress. MERS-CoV-infected common marmosets treated with mycophenolate mofetil developed a fatal infection with even higher viral loads in their lungs and extrapulmonary tissues than untreated controls did<sup><xref ref-type="bibr" rid="CR128">128</xref>
</sup>
. Agents targeting host signalling pathways or receptors may induce immunopathology. Furthermore, the lack of a reliable drug delivery method <italic>in vivo</italic>
is particularly problematic for siRNAs and other agents that have not been previously used in humans.</p>
<p id="Par58">Looking ahead, the most feasible options that should be further evaluated in clinical trials for the ongoing MERS epidemic include monotherapy or combinational therapies that include lopinavir–ritonavir, interferon beta-1b and/or mAbs and antiviral peptides targeting MERS-CoV S. These agents have protective effects against MERS in non-human primate or mouse models. Moreover, they are either marketed drugs (in the case of lopinavir–ritonavir and interferon beta-1b) or they have been successfully developed for other infections (such as palivizumab, which is used for respiratory syncytial virus infection, and enfuvirtide, which is used for HIV infection). In the long term, the development of novel, broad-spectrum, pan-CoV antiviral drugs that are active against a wide range of CoVs may become the ultimate treatment strategy for circulating and emerging CoV infections.</p>
</sec>
<sec sec-type="supplementary-material"><title>Supplementary information</title>
<sec id="Sec9"><p><supplementary-material content-type="local-data" id="MOESM12"><media xlink:href="41573_2016_BFnrd201537_MOESM12_ESM.pdf"><caption><title>Supplementary information S1 (figure)</title>
<p>Global Distribution of SARS and MERS (PDF 1587 kb)</p>
</caption>
</media>
</supplementary-material>
</p>
<p><supplementary-material content-type="local-data" id="MOESM13"><media xlink:href="41573_2016_BFnrd201537_MOESM13_ESM.pdf"><caption><title>Supplementary information S2 (table)</title>
<p>Comparisons of the clinical and laboratory features between SARS and MERS (PDF 139 kb)</p>
</caption>
</media>
</supplementary-material>
</p>
</sec>
</sec>
</body>
<back><app-group><app id="App1"><sec id="Sec10"><title>PowerPoint slides</title>
<p id="Par62"><media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM6_ESM.ppt" id="MOESM6"><caption><p>PowerPoint slide for Fig. 1</p>
</caption>
</media>
<media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM7_ESM.ppt" id="MOESM7"><caption><p>PowerPoint slide for Fig. 2</p>
</caption>
</media>
</p>
<p id="Par63"><media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM8_ESM.ppt" id="MOESM8"><caption><p>PowerPoint slide for Table 1</p>
</caption>
</media>
<media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM9_ESM.ppt" id="MOESM9"><caption><p>PowerPoint slide for Table 2</p>
</caption>
</media>
<media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM10_ESM.ppt" id="MOESM10"><caption><p>PowerPoint slide for Table 3</p>
</caption>
</media>
<media position="anchor" xlink:href="41573_2016_BFnrd201537_MOESM11_ESM.ppt" id="MOESM11"><caption><p>PowerPoint slide for Table 4</p>
</caption>
</media>
</p>
</sec>
</app>
</app-group>
<fn-group><fn><p>Alimuddin Zumla, Jasper F. W. Chan, Esam I. Azhar, David S. C. Hui and Kwok-Yung Yuen: All authors contributed equally to this work.</p>
</fn>
</fn-group>
<ack><title>Acknowledgements</title>
<p>The research of J. F.-W. C. and K.-Y. Y. is partly supported by funding from Respiratory Viral Research Foundation Limited; the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Disease of the Department of Health; the Health and Medical Research Fund (15140762) of the Food and Health Bureau; the National Natural Science Foundation of China/Research Grants Council Joint Research Scheme (N_HKU728/14); and the Theme-based Research Scheme (T11 707/15 R) of the Research Grants Council, Hong Kong Special Administrative Region of the People's Republic of China. A.Z. acknowledges support from the National Institutes of Health Research (NIHR), Biomedical Research Centre at UCL Hospital, London, UK. The funding sources had no role in study design, data collection, analysis, or interpretation or writing of the report.</p>
</ack>
<notes notes-type="COI-statement"><title>Competing interests</title>
<p id="Par59">J. F.-W. C. has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong Corporation Limited. The funding sources had no role in study design, data collection, analysis or interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.</p>
</notes>
<glossary><title>Glossary</title>
<def-list><def-item id="Glos1"><term>Zoonotic virus</term>
<def><p>A virus that can transmit an infectious disease from animals (usually vertebrates) to humans.</p>
</def>
</def-item>
<def-item id="Glos2"><term>Spike glycoprotein (S)</term>
<def><p>A major immunogenic antigen of coronaviruses that is essential for interactions between a virus and host cell receptor, and is an important therapeutic target.</p>
</def>
</def-item>
<def-item id="Glos3"><term>Syncytium</term>
<def><p>A multinucleated cell resulting from the fusion of the host membranes of neighbouring cells infected by various viruses, including CoVs.</p>
</def>
</def-item>
<def-item id="Glos4"><term>Convalescent-phase plasma</term>
<def><p>Plasma that contains neutralizing antibodies against a microorganism and is obtained from patients recovering from the infection.</p>
</def>
</def-item>
<def-item id="Glos5"><term>Viroporin</term>
<def><p>A small integral membrane protein that is localized primarily within the endoplasmic reticulum and plasma membranes of host cells, and has the characteristic ability to form ion channels or pores.</p>
</def>
</def-item>
<def-item id="Glos6"><term>Protein cage nanoparticles</term>
<def><p>Nanoscale delivery platforms, made of biomaterials and/or proteins, that are used for various biomedical applications including the delivery of therapeutic cargo molecules.</p>
</def>
</def-item>
<def-item id="Glos7"><term>Koch's postulates</term>
<def><p>Criteria used to establish a causative relationship between a microorganism and a disease.</p>
</def>
</def-item>
</def-list>
</glossary>
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