The Use of Antimalarial Drugs against Viral Infection
Identifieur interne : 000A65 ( Pmc/Corpus ); précédent : 000A64; suivant : 000A66The Use of Antimalarial Drugs against Viral Infection
Auteurs : Sarah D Lessandro ; Diletta Scaccabarozzi ; Lucia Signorini ; Federica Perego ; Denise P. Ilboudo ; Pasquale Ferrante ; Serena DelbueSource :
- Microorganisms [ 2076-2607 ] ; 2020.
Abstract
In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.
Url:
DOI: 10.3390/microorganisms8010085
PubMed: 31936284
PubMed Central: 7022795
Links to Exploration step
PMC:7022795Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Use of Antimalarial Drugs against Viral Infection</title><author><name sortKey="D Lessandro, Sarah" sort="D Lessandro, Sarah" uniqKey="D Lessandro S" first="Sarah" last="D Lessandro">Sarah D Lessandro</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Scaccabarozzi, Diletta" sort="Scaccabarozzi, Diletta" uniqKey="Scaccabarozzi D" first="Diletta" last="Scaccabarozzi">Diletta Scaccabarozzi</name><affiliation><nlm:aff id="af2-microorganisms-08-00085">Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milan, Italy;<email>diletta.scaccabarozzi@unimi.it</email></nlm:aff></affiliation></author><author><name sortKey="Signorini, Lucia" sort="Signorini, Lucia" uniqKey="Signorini L" first="Lucia" last="Signorini">Lucia Signorini</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Perego, Federica" sort="Perego, Federica" uniqKey="Perego F" first="Federica" last="Perego">Federica Perego</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Ilboudo, Denise P" sort="Ilboudo, Denise P" uniqKey="Ilboudo D" first="Denise P." last="Ilboudo">Denise P. Ilboudo</name><affiliation><nlm:aff id="af3-microorganisms-08-00085">Département des Sciences de la Vie, University of Fada N’Gourma (UFDG), Fada N’Gourma BP 54, Burkina Faso;<email>denise.ilboudo@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Ferrante, Pasquale" sort="Ferrante, Pasquale" uniqKey="Ferrante P" first="Pasquale" last="Ferrante">Pasquale Ferrante</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Delbue, Serena" sort="Delbue, Serena" uniqKey="Delbue S" first="Serena" last="Delbue">Serena Delbue</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31936284</idno><idno type="pmc">7022795</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022795</idno><idno type="RBID">PMC:7022795</idno><idno type="doi">10.3390/microorganisms8010085</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000A65</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A65</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Use of Antimalarial Drugs against Viral Infection</title><author><name sortKey="D Lessandro, Sarah" sort="D Lessandro, Sarah" uniqKey="D Lessandro S" first="Sarah" last="D Lessandro">Sarah D Lessandro</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Scaccabarozzi, Diletta" sort="Scaccabarozzi, Diletta" uniqKey="Scaccabarozzi D" first="Diletta" last="Scaccabarozzi">Diletta Scaccabarozzi</name><affiliation><nlm:aff id="af2-microorganisms-08-00085">Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milan, Italy;<email>diletta.scaccabarozzi@unimi.it</email></nlm:aff></affiliation></author><author><name sortKey="Signorini, Lucia" sort="Signorini, Lucia" uniqKey="Signorini L" first="Lucia" last="Signorini">Lucia Signorini</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Perego, Federica" sort="Perego, Federica" uniqKey="Perego F" first="Federica" last="Perego">Federica Perego</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Ilboudo, Denise P" sort="Ilboudo, Denise P" uniqKey="Ilboudo D" first="Denise P." last="Ilboudo">Denise P. Ilboudo</name><affiliation><nlm:aff id="af3-microorganisms-08-00085">Département des Sciences de la Vie, University of Fada N’Gourma (UFDG), Fada N’Gourma BP 54, Burkina Faso;<email>denise.ilboudo@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Ferrante, Pasquale" sort="Ferrante, Pasquale" uniqKey="Ferrante P" first="Pasquale" last="Ferrante">Pasquale Ferrante</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author><author><name sortKey="Delbue, Serena" sort="Delbue, Serena" uniqKey="Delbue S" first="Serena" last="Delbue">Serena Delbue</name><affiliation><nlm:aff id="af1-microorganisms-08-00085">Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</nlm:aff></affiliation></author></analytic><series><title level="j">Microorganisms</title><idno type="eISSN">2076-2607</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Haladyj, E" uniqKey="Haladyj E">E. Haładyj</name></author><author><name sortKey="Sikora, M" uniqKey="Sikora M">M. Sikora</name></author><author><name sortKey="Felis Giemza, A" uniqKey="Felis Giemza A">A. Felis-Giemza</name></author><author><name sortKey="Olesi Ska, M" uniqKey="Olesi Ska M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Microorganisms</journal-id><journal-id journal-id-type="iso-abbrev">Microorganisms</journal-id><journal-id journal-id-type="publisher-id">microorganisms</journal-id><journal-title-group><journal-title>Microorganisms</journal-title></journal-title-group><issn pub-type="epub">2076-2607</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31936284</article-id><article-id pub-id-type="pmc">7022795</article-id><article-id pub-id-type="doi">10.3390/microorganisms8010085</article-id><article-id pub-id-type="publisher-id">microorganisms-08-00085</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>The Use of Antimalarial Drugs against Viral Infection</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9241-9762</contrib-id><name><surname>D’Alessandro</surname><given-names>Sarah</given-names></name><xref ref-type="aff" rid="af1-microorganisms-08-00085">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-8881-898X</contrib-id><name><surname>Scaccabarozzi</surname><given-names>Diletta</given-names></name><xref ref-type="aff" rid="af2-microorganisms-08-00085">2</xref></contrib><contrib contrib-type="author"><name><surname>Signorini</surname><given-names>Lucia</given-names></name><xref ref-type="aff" rid="af1-microorganisms-08-00085">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-1566-0231</contrib-id><name><surname>Perego</surname><given-names>Federica</given-names></name><xref ref-type="aff" rid="af1-microorganisms-08-00085">1</xref></contrib><contrib contrib-type="author"><name><surname>Ilboudo</surname><given-names>Denise P.</given-names></name><xref ref-type="aff" rid="af3-microorganisms-08-00085">3</xref></contrib><contrib contrib-type="author"><name><surname>Ferrante</surname><given-names>Pasquale</given-names></name><xref ref-type="aff" rid="af1-microorganisms-08-00085">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-3199-9369</contrib-id><name><surname>Delbue</surname><given-names>Serena</given-names></name><xref ref-type="aff" rid="af1-microorganisms-08-00085">1</xref><xref rid="c1-microorganisms-08-00085" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-microorganisms-08-00085"><label>1</label>Department of Biomedical, Surgical and Dental Sciences, University of Milano, 20133 Milan, Italy;<email>sarah.dalessandro@unimi.it</email> (S.D.);<email>lucia.signorini@unimi.it</email> (L.S.);<email>federica.perego@unimi.it</email> (F.P.);<email>pasquale.ferrante@unimi.it</email> (P.F.)</aff><aff id="af2-microorganisms-08-00085"><label>2</label>Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milan, Italy;<email>diletta.scaccabarozzi@unimi.it</email></aff><aff id="af3-microorganisms-08-00085"><label>3</label>Département des Sciences de la Vie, University of Fada N’Gourma (UFDG), Fada N’Gourma BP 54, Burkina Faso;<email>denise.ilboudo@gmail.com</email></aff><author-notes><corresp id="c1-microorganisms-08-00085"><label>*</label>Correspondence: <email>serena.delbue@unimi.it</email>; Tel.: +39-02-50315070</corresp></author-notes><pub-date pub-type="epub"><day>08</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>8</volume><issue>1</issue><elocation-id>85</elocation-id><history><date date-type="received"><day>11</day><month>12</month><year>2019</year></date><date date-type="accepted"><day>03</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (i.e., HIV, dengue virus, chikungunya virus, Ebola virus, etc.) or against classic infections due to drug-resistant viral strains (i.e., human cytomegalovirus). Here, we reviewed the in vitro/in vivo and clinical studies conducted to evaluate the antiviral activities of four classes of antimalarial drugs: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs.</p></abstract><kwd-group><kwd>antimalarial drugs</kwd><kwd>viruses</kwd><kwd>emerging infections</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-microorganisms-08-00085"><title>1. Introduction</title><p>Antimalarial drugs used for the treatment and prevention of malaria are classified in a heterogenic group [<xref rid="B1-microorganisms-08-00085" ref-type="bibr">1</xref>]. They are usually divided based on the chemical structure or the source of the drugs. Most of them derive from traditional medicine and plants. After identification of the active principles, chemical modifications are introduced to increase the activity and ameliorate the selectivity index. They present different modes and various mechanisms of action, which are often still not elucidated, against malaria parasites. Furthermore, due to the complexity of these molecules, additional side activities have been reported. For these reasons, antimalarial drugs have been studied, proposed, and sometimes used for the treatment of other pathologies, such as cancer, autoimmune diseases, and nonmalaria infectious diseases [<xref rid="B2-microorganisms-08-00085" ref-type="bibr">2</xref>,<xref rid="B3-microorganisms-08-00085" ref-type="bibr">3</xref>,<xref rid="B4-microorganisms-08-00085" ref-type="bibr">4</xref>]. Moreover, the geographical overlaps between malaria and viral-related diseases [<xref rid="B5-microorganisms-08-00085" ref-type="bibr">5</xref>,<xref rid="B6-microorganisms-08-00085" ref-type="bibr">6</xref>,<xref rid="B7-microorganisms-08-00085" ref-type="bibr">7</xref>] have led to the consideration of possible use of antimalarial drugs as new antiviral drugs. Finally, the lack of new effective antiviral drugs and vaccines against many viral infections has strengthened interest in the potential antiviral activity of antimalarial drugs.</p><p>In the present review, the authors present the use and the efficacy against human viruses of the principal antimalarial drugs, divided into four main groups: Artemisinin derivatives, aryl-aminoalcohols, aminoquinolines, and antimicrobial drugs. The chemical structures of the cited compounds are summarized in <xref ref-type="fig" rid="microorganisms-08-00085-f001">Figure 1</xref>. Works on newly synthesized derivatives, which are not licensed, were not taken into consideration. When possible, original manuscripts were cited. However, previous works of other scientists were acknowledged also by citing review articles, aiming to provide a comprehensive list of published papers on the proposed field.</p></sec><sec id="sec2-microorganisms-08-00085"><title>2. Artemisinin Derivatives</title><p><italic>Artemisia annua</italic> (qinghao) is a plant of the <italic>Asteraceae</italic> family, which has been used for ages in traditional Chinese medicine [<xref rid="B8-microorganisms-08-00085" ref-type="bibr">8</xref>]. The sesquiterpene lactone artemisinin (ART), the active principle, was discovered in the 1970s. Since then, chemical structural modification studies have been performed to obtain new compounds with enhanced antimalarial activity and improved pharmacological properties. ART derivatives are safe and well-tolerated drugs. This safety is one of the reasons why they have been studied for their efficacy in other diseases beyond malaria. ART derivatives are active against other parasites, cancer cells and viruses, although with lower potency, with effective concentration<sub>50s</sub> (EC<sub>50</sub>s) in the micromolar range, compared to the nanomolar range as antimalarials [<xref rid="B9-microorganisms-08-00085" ref-type="bibr">9</xref>].</p><p>The majority of the literature describes the antiviral effect of ART derivatives in vitro toward human cytomegalovirus (HCMV). A large contribution to the field was given by Thomas Efferth and his collaborators, with both original research articles [<xref rid="B10-microorganisms-08-00085" ref-type="bibr">10</xref>,<xref rid="B11-microorganisms-08-00085" ref-type="bibr">11</xref>,<xref rid="B12-microorganisms-08-00085" ref-type="bibr">12</xref>,<xref rid="B13-microorganisms-08-00085" ref-type="bibr">13</xref>] and reviews [<xref rid="B14-microorganisms-08-00085" ref-type="bibr">14</xref>,<xref rid="B15-microorganisms-08-00085" ref-type="bibr">15</xref>].</p><sec id="sec2dot1-microorganisms-08-00085"><title>2.1. Artemisinin</title><p>ART, the active principle extracted from <italic>Artemisia annua</italic>, is poorly soluble in water and oil, thus, the development of semisynthetic derivatives was necessary for appropriate formulation. Poor physicochemical properties may account for the scarce literature about the use of ART as an antiviral. ART, dihydroartemisinin (DHA) and artesunate (AS) were compared for their anti-HCMV effect in a fibroblast cell model by measuring viral DNA synthesis in cellular lysates. ART showed the lowest activity, even when fractional doses and daily repeated administration were used to counteract the problem of instability of the compounds in a culture medium [<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>]. Compared to other compounds from traditional Chinese medicine, ART and AS were also the most active, with low toxicity, for the inhibition of the hepatitis B virus (HBV), measured by hepatitis B surface antigen (HBsAg) and DNA release in a culture medium. Moreover, synergism with the antiviral lamivudine was demonstrated [<xref rid="B17-microorganisms-08-00085" ref-type="bibr">17</xref>]. ART downregulated the oncogenic human papillomavirus (HPV) 39 proteins E6 and E7 in an in vitro model of cervical carcinoma [<xref rid="B18-microorganisms-08-00085" ref-type="bibr">18</xref>]. These results partially confirmed the report by Disbrow and colleagues, who observed an antiproliferative effect of DHA on canine oral papillomavirus [<xref rid="B19-microorganisms-08-00085" ref-type="bibr">19</xref>].</p><p>ART also inhibits hepatitis C virus (HCV) replicon replication [<xref rid="B20-microorganisms-08-00085" ref-type="bibr">20</xref>], and the effect is synergistic with hemin, an iron donor [<xref rid="B21-microorganisms-08-00085" ref-type="bibr">21</xref>,<xref rid="B22-microorganisms-08-00085" ref-type="bibr">22</xref>].</p><p>Finally, ART showed inhibition of human immunodeficiency virus (HIV) replication, but the effect was not reproducible in different cell models [<xref rid="B23-microorganisms-08-00085" ref-type="bibr">23</xref>].</p></sec><sec id="sec2dot2-microorganisms-08-00085"><title>2.2. Artesunate</title><sec id="sec2dot2dot1-microorganisms-08-00085"><title>2.2.1. Artesunate and HCMV</title><p>The activity of AS on the replication of HCMV was demonstrated in different in vitro cell models, such as fibroblasts [<xref rid="B11-microorganisms-08-00085" ref-type="bibr">11</xref>,<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>,<xref rid="B24-microorganisms-08-00085" ref-type="bibr">24</xref>] and tumor cells [<xref rid="B25-microorganisms-08-00085" ref-type="bibr">25</xref>,<xref rid="B26-microorganisms-08-00085" ref-type="bibr">26</xref>]. Compared to other ART derivatives, AS had the highest activity [<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>,<xref rid="B27-microorganisms-08-00085" ref-type="bibr">27</xref>] and an activity comparable to or even higher than that of classical antiviral drugs, such as ganciclovir [<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>,<xref rid="B25-microorganisms-08-00085" ref-type="bibr">25</xref>,<xref rid="B28-microorganisms-08-00085" ref-type="bibr">28</xref>]. The antiviral effect was confirmed against different, multidrug-resistant strains [<xref rid="B10-microorganisms-08-00085" ref-type="bibr">10</xref>,<xref rid="B25-microorganisms-08-00085" ref-type="bibr">25</xref>,<xref rid="B27-microorganisms-08-00085" ref-type="bibr">27</xref>,<xref rid="B29-microorganisms-08-00085" ref-type="bibr">29</xref>] and with different methods, such as the plaque assay and luminescent/fluorescent methods based on the use of transgenic viral strains [<xref rid="B24-microorganisms-08-00085" ref-type="bibr">24</xref>,<xref rid="B30-microorganisms-08-00085" ref-type="bibr">30</xref>,<xref rid="B31-microorganisms-08-00085" ref-type="bibr">31</xref>]. In some cases, the effect of AS was synergistic with antiviral drugs such as maribavir [<xref rid="B27-microorganisms-08-00085" ref-type="bibr">27</xref>,<xref rid="B32-microorganisms-08-00085" ref-type="bibr">32</xref>,<xref rid="B33-microorganisms-08-00085" ref-type="bibr">33</xref>], lamivudine [<xref rid="B17-microorganisms-08-00085" ref-type="bibr">17</xref>], ganciclovir [<xref rid="B34-microorganisms-08-00085" ref-type="bibr">34</xref>], foscarnet, cidofovir, letermovir [<xref rid="B33-microorganisms-08-00085" ref-type="bibr">33</xref>]. However, in vitro data regarding synergism are not always confirmed in other experimental conditions, as for the case reported by Morère, where synergism between maribavir and AS was not confirmed in an ex vivo placenta model [<xref rid="B32-microorganisms-08-00085" ref-type="bibr">32</xref>]. Moreover, few data obtained with animal models are available. In the rat CMV/rat model, AS demonstrated antiviral activity, measured as the dissemination of virus to the salivary glands, the number of viral genome copies, and virus titers in salivary glands. This activity was exerted only when AS was coadministered with iron in the Ferrosanol™ formulation [<xref rid="B11-microorganisms-08-00085" ref-type="bibr">11</xref>]. AS in association with valacyclovir was tested in a murine model of herpes simplex virus encephalitis (HSE) to evaluate not only the antiviral but also the immunomodulating activity, which would be beneficial in this disease model. The survival rates of mice treated with both drugs were higher than those of mice treated with valacyclovir alone, but no significant difference was observed in the brain viral loads. Levels of cytokines such as Interleukine (IL)-1β, IL-2, IL-6, Interferon (IFN)-γ, and CCL2 were reduced in mice treated with valacyclovir combined with ART versus those in mice treated with valacyclovir alone [<xref rid="B35-microorganisms-08-00085" ref-type="bibr">35</xref>].</p><p>Clinical data supporting the use of AS against HCMV are contrasting. In a case report, a rapid decrease in viral load was observed in a stem cell transplant recipient infected with a newly identified foscarnet-resistant and ganciclovir-resistant HCMV strain and treated with AS [<xref rid="B12-microorganisms-08-00085" ref-type="bibr">12</xref>]. In this regard, a clinical trial was registered for the use of AS in stem cell transplant recipients, but although the recruitment of 20 patients in Israel has been completed, no results are available yet (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>).</p><p>On the other hand, a renal transplant recipient patient with documented valganciclovir resistance mutations in HCMV was treated with AS, with no positive effects [<xref rid="B46-microorganisms-08-00085" ref-type="bibr">46</xref>]. A third case report of a patient with multidrug-resistant HCMV infection is difficult to interpret due to the complicated series of treatments after two hematopoietic stem cell transplantations and consequent acute graft-versus-host disease episodes. In this patient, AS given in association with maribavir was withdrawn two weeks after initiation because of orthostatic hypotension [<xref rid="B47-microorganisms-08-00085" ref-type="bibr">47</xref>]. Wolf and colleagues described six cases of stem cell transplant recipients who received pre-emptive AS treatment for HCMV infection. Two of these showed a decrease in the viral load [<xref rid="B13-microorganisms-08-00085" ref-type="bibr">13</xref>]. In another study, five transplanted patients infected with HCMV strains resistant to different antiviral drugs were treated with AS after many unsuccessful cycles of antiviral treatments. Three out of five had a favorable outcome [<xref rid="B48-microorganisms-08-00085" ref-type="bibr">48</xref>].</p><p>At present, ART derivatives are recommended as antimalarial treatments in combination with another molecule with a different mechanism of action and longer half-life (ART combination therapy, ACT) to avoid the onset of resistance and to prevent recrudescence. One of these combinations, AS plus amodiaquine (AQ), was tested against HCMV in a clinical study conducted on 494 Ugandan children treated for acute malaria either with the ACT or with sulfadoxine–pyrimethamine plus AQ. No measurable difference was observed in either the HCMV detection frequency or load in the blood of children in the two groups [<xref rid="B49-microorganisms-08-00085" ref-type="bibr">49</xref>].</p></sec><sec id="sec2dot2dot2-microorganisms-08-00085"><title>2.2.2. Artesunate and Other Viruses</title><p>AS was effective at a low micromolar range against Epstein Barr virus (EBV) in both epithelial cells and lymphocytes [<xref rid="B50-microorganisms-08-00085" ref-type="bibr">50</xref>]. Antiviral activity against human herpes virus-6 (HHV-6) was demonstrated not only in vitro [<xref rid="B51-microorganisms-08-00085" ref-type="bibr">51</xref>] but also in a child affected by HHV-6B-associated myocarditis. AS treatment was associated with a decrease in the levels of HHV-6B DNA in the myocardium [<xref rid="B52-microorganisms-08-00085" ref-type="bibr">52</xref>]. However, data on the effect of AS against HHV-6 are contrasting in the literature [<xref rid="B53-microorganisms-08-00085" ref-type="bibr">53</xref>].</p><p>AS affects human BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV) replication in vitro [<xref rid="B54-microorganisms-08-00085" ref-type="bibr">54</xref>,<xref rid="B55-microorganisms-08-00085" ref-type="bibr">55</xref>]. Both viruses latently and asymptomatically infect the human host and are able to reactivate in immunosuppressed hosts, such as HIV-positive patients or transplant recipients. JCPyV causes a rare and fatal disease known as progressive multifocal leukoencephalopathy (PML), while BKPyV is associated with nephropathy [<xref rid="B56-microorganisms-08-00085" ref-type="bibr">56</xref>].</p><p>As mentioned above, ART and AS were more active against HBV and less toxic than other compounds from traditional Chinese medicine [<xref rid="B17-microorganisms-08-00085" ref-type="bibr">17</xref>]. The reduction in HCV replicons caused by AS was dose and time-dependent in vitro and increased when AS was given in association with IFN [<xref rid="B57-microorganisms-08-00085" ref-type="bibr">57</xref>].</p><p>Interestingly, in the USA, an open-label study is currently investigating a novel nonsurgical approach to the treatment of HPV-associated anal intraepithelial high-grade neoplasia using AS suppositories. The outcomes that will be verified will be the regression of the lesions and the clearance of HPV. Similarly, a phase II double-blind, placebo-controlled, randomized study of AS vaginal inserts has been designed for the treatment of women who have cervical high-grade intraepithelial neoplasia, but recruitment has not yet started (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>).</p><p>Finally, the combination AS-AQ was also used in patients infected with the Ebola virus (EBOV), reducing the mortality risk more than the other ACT used (artemether-lumefantrine) [<xref rid="B58-microorganisms-08-00085" ref-type="bibr">58</xref>]. However, moderate to serious risk of bias and small sample sizes preclude conclusions [<xref rid="B59-microorganisms-08-00085" ref-type="bibr">59</xref>]. During the EBOV disease epidemic in West Africa in 2014–2016, two mass drug administrations of AS-AQ were implemented to decrease the burden of malaria. Garbern and colleagues performed a retrospective study to assess the potential effect of this treatment on the mortality of patients with EBOV. Although the risk of mortality for treated patients compared to that of EBOV infected patients not exposed to AS-AQ was decreased, the effect was not significant. Prospective trials are needed [<xref rid="B60-microorganisms-08-00085" ref-type="bibr">60</xref>].</p></sec></sec><sec id="sec2dot3-microorganisms-08-00085"><title>2.3. Other Artemisinin Derivatives</title><p>The activity of different ART derivatives was evaluated against HCMV in a fibroblast model using a luminescent assay based on transgenic viral strain. Compared to AS and/or ART, artemether was the most active. However, the activity was only seen at the micromolar range of concentrations, and only the synthesis of dimers allowed the activity to be effective at nanomolar concentrations [<xref rid="B61-microorganisms-08-00085" ref-type="bibr">61</xref>,<xref rid="B62-microorganisms-08-00085" ref-type="bibr">62</xref>].</p><p>DHA is the active metabolite of most ART derivatives and an antimalarial drug itself. DHA and ART were tested against bovine viral diarrhea virus (BVDV), a surrogate in vitro model of HCV, showing moderate activity in the micromolar concentration range [<xref rid="B63-microorganisms-08-00085" ref-type="bibr">63</xref>].</p><p>Artemether is often used in combination with lumefantrine. One of the commercial versions of this combination, Coartem<sup>®</sup>, was used in a prospective observational study in Mali in children (6 months–10 years) coinfected with HCMV and malaria. Viral load in the urine decreased but only in high virus shedders [<xref rid="B64-microorganisms-08-00085" ref-type="bibr">64</xref>]. The artemether-lumefantrine combination was also used in patients infected with EBOV, showing reduced efficacy in reducing the risk of death compared to that of AS-AQ, as already described in the “Artesunate” paragraph [<xref rid="B58-microorganisms-08-00085" ref-type="bibr">58</xref>].</p></sec></sec><sec id="sec3-microorganisms-08-00085"><title>3. Aryl-Aminoalcohols</title><p>The antiviral effect of the aryl-aminoalcohol compounds quinine sulfate, mefloquine, halofantrine, and lumefantrine on both classical and emerging viruses has been studied.</p><sec id="sec3dot1-microorganisms-08-00085"><title>3.1. Quinine Sulfate</title><p>Quinine, an alkaloid extract from <italic>Chinchona</italic> (quina-quina) tree bark, was discovered in the 17th century and has been used to treat malaria since the early 1600s, currently still playing a pivotal role, especially in the treatment of chloroquine (CQ)-resistant <italic>Plasmodium falciparum</italic> [<xref rid="B65-microorganisms-08-00085" ref-type="bibr">65</xref>,<xref rid="B66-microorganisms-08-00085" ref-type="bibr">66</xref>]. Due to the benefit derived from antimalarial drugs in other pathologies, possible antiviral effects of quinine were investigated.</p><p>The first manuscript regarding the effect of quinine on influenza virus infections in mice was published in 1946 [<xref rid="B67-microorganisms-08-00085" ref-type="bibr">67</xref>].</p><p>Subsequently, in vitro evaluation of quinine sulfate has been conducted with other viruses, such as herpes simplex virus-1 (HSV-1) and influenza A virus (IAV). Quinine sulfate at micromolar but not toxic doses reduced the number of plaques formed by HSV-1 in vitro in Vero and HaCaT cell models, although no viricidal activity was observed [<xref rid="B68-microorganisms-08-00085" ref-type="bibr">68</xref>,<xref rid="B69-microorganisms-08-00085" ref-type="bibr">69</xref>]. Quinine sulfate in vitro activity was also tested against IAV by means of viral plaque inhibition assay, evaluating its prophylactic activity and showing different effects with an EC<sub>50</sub> within the micromolar range, depending on the viral strains [<xref rid="B70-microorganisms-08-00085" ref-type="bibr">70</xref>]. Recently, quinine sulfate was tested in vitro against emerging dengue virus (DENV) strains in different cell lines, showing a reduction in DENV-2 virion production up to 80% compared to that of the untreated control and a concentration-dependent reduction in DENV RNA and viral proteins. The inhibition of replication was then confirmed for all four different serotypes of DENV [<xref rid="B66-microorganisms-08-00085" ref-type="bibr">66</xref>].</p></sec><sec id="sec3dot2-microorganisms-08-00085"><title>3.2. Mefloquine</title><sec id="sec3dot2dot1-microorganisms-08-00085"><title>3.2.1. Mefloquine and JCPyV</title><p>Mefloquine (MQ), a synthetic analog of quinine with a long history of use and good safety in humans, has been widely tested as an antiviral. One of the first reports refers to JCPyV. In 2009, Brickelmaier et al. chose MQ because of its high blood-brain barrier penetration capability since it accumulates in brain tissue at a six-fold higher concentration than its EC<sub>50</sub>. MQ was active against different strains of JCPyV in three different cell models, with EC<sub>50</sub>s within the low micromolar range [<xref rid="B71-microorganisms-08-00085" ref-type="bibr">71</xref>]. Because of the absence of a suitable animal model, this first paper represented the starting point for a series of trials in human populations, which obtained contrasting results and are summarized in <xref rid="microorganisms-08-00085-t002" ref-type="table">Table 2</xref>. Seventeen case reports described the use of MQ at different doses [<xref rid="B72-microorganisms-08-00085" ref-type="bibr">72</xref>,<xref rid="B73-microorganisms-08-00085" ref-type="bibr">73</xref>,<xref rid="B74-microorganisms-08-00085" ref-type="bibr">74</xref>,<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>,<xref rid="B76-microorganisms-08-00085" ref-type="bibr">76</xref>,<xref rid="B77-microorganisms-08-00085" ref-type="bibr">77</xref>,<xref rid="B78-microorganisms-08-00085" ref-type="bibr">78</xref>,<xref rid="B79-microorganisms-08-00085" ref-type="bibr">79</xref>,<xref rid="B80-microorganisms-08-00085" ref-type="bibr">80</xref>,<xref rid="B81-microorganisms-08-00085" ref-type="bibr">81</xref>,<xref rid="B82-microorganisms-08-00085" ref-type="bibr">82</xref>,<xref rid="B83-microorganisms-08-00085" ref-type="bibr">83</xref>,<xref rid="B84-microorganisms-08-00085" ref-type="bibr">84</xref>,<xref rid="B85-microorganisms-08-00085" ref-type="bibr">85</xref>,<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B88-microorganisms-08-00085" ref-type="bibr">88</xref>]. Although in 12 cases there was no progression of the disease at follow-up [<xref rid="B72-microorganisms-08-00085" ref-type="bibr">72</xref>,<xref rid="B73-microorganisms-08-00085" ref-type="bibr">73</xref>,<xref rid="B74-microorganisms-08-00085" ref-type="bibr">74</xref>,<xref rid="B77-microorganisms-08-00085" ref-type="bibr">77</xref>,<xref rid="B78-microorganisms-08-00085" ref-type="bibr">78</xref>,<xref rid="B79-microorganisms-08-00085" ref-type="bibr">79</xref>,<xref rid="B81-microorganisms-08-00085" ref-type="bibr">81</xref>,<xref rid="B82-microorganisms-08-00085" ref-type="bibr">82</xref>,<xref rid="B83-microorganisms-08-00085" ref-type="bibr">83</xref>,<xref rid="B84-microorganisms-08-00085" ref-type="bibr">84</xref>,<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>], it is difficult to draw conclusions due to the challenging treatment protocols and compromised health of the patients. In many cases, MQ was combined with mirtazapine, an antidepressant that, acting on the 5-HT2A serotonin receptor, is able to inhibit JCPyV entry into glial cells, preventing the diffusion of the infection in oligodendrocytes. The outcomes of this treatment are controversial, leading to the resolution of the infection, with a claimed effect of MQ and mirtazapine treatment [<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B89-microorganisms-08-00085" ref-type="bibr">89</xref>,<xref rid="B90-microorganisms-08-00085" ref-type="bibr">90</xref>,<xref rid="B91-microorganisms-08-00085" ref-type="bibr">91</xref>,<xref rid="B92-microorganisms-08-00085" ref-type="bibr">92</xref>,<xref rid="B93-microorganisms-08-00085" ref-type="bibr">93</xref>,<xref rid="B94-microorganisms-08-00085" ref-type="bibr">94</xref>,<xref rid="B95-microorganisms-08-00085" ref-type="bibr">95</xref>,<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B97-microorganisms-08-00085" ref-type="bibr">97</xref>,<xref rid="B98-microorganisms-08-00085" ref-type="bibr">98</xref>,<xref rid="B99-microorganisms-08-00085" ref-type="bibr">99</xref>,<xref rid="B100-microorganisms-08-00085" ref-type="bibr">100</xref>,<xref rid="B101-microorganisms-08-00085" ref-type="bibr">101</xref>,<xref rid="B102-microorganisms-08-00085" ref-type="bibr">102</xref>,<xref rid="B103-microorganisms-08-00085" ref-type="bibr">103</xref>,<xref rid="B104-microorganisms-08-00085" ref-type="bibr">104</xref>,<xref rid="B105-microorganisms-08-00085" ref-type="bibr">105</xref>], and to the resolution of the infection probably due to other factors [<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B106-microorganisms-08-00085" ref-type="bibr">106</xref>,<xref rid="B107-microorganisms-08-00085" ref-type="bibr">107</xref>,<xref rid="B108-microorganisms-08-00085" ref-type="bibr">108</xref>,<xref rid="B109-microorganisms-08-00085" ref-type="bibr">109</xref>] or to the death of the patient, which was not always directly related to the unsuccessful therapy [<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B110-microorganisms-08-00085" ref-type="bibr">110</xref>,<xref rid="B111-microorganisms-08-00085" ref-type="bibr">111</xref>,<xref rid="B112-microorganisms-08-00085" ref-type="bibr">112</xref>,<xref rid="B113-microorganisms-08-00085" ref-type="bibr">113</xref>,<xref rid="B114-microorganisms-08-00085" ref-type="bibr">114</xref>,<xref rid="B115-microorganisms-08-00085" ref-type="bibr">115</xref>,<xref rid="B116-microorganisms-08-00085" ref-type="bibr">116</xref>]. In one case, the suspension of the therapy was necessary due to the side effects [<xref rid="B117-microorganisms-08-00085" ref-type="bibr">117</xref>]. In a few cases, a third partner drug was added to MQ and mirtazapine. Again, the outcome was variable, and the contribution of the single drugs was difficult to determine [<xref rid="B118-microorganisms-08-00085" ref-type="bibr">118</xref>,<xref rid="B119-microorganisms-08-00085" ref-type="bibr">119</xref>].</p><p>MQ has also been combined with risperidone [<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>] or risperidone and cytarabine [<xref rid="B120-microorganisms-08-00085" ref-type="bibr">120</xref>], and the final outcomes were opposing, either death or recovery of the patient.</p><p>In one case, MQ was administered with the antiviral cidofovir, resulting in final remission of the pathology, most likely due to synergy with other factors [<xref rid="B121-microorganisms-08-00085" ref-type="bibr">121</xref>].</p><p>Different case reports have described the use of MQ by itself in HIV-positive PML patients, sometimes with repression of JCPyV replication [<xref rid="B122-microorganisms-08-00085" ref-type="bibr">122</xref>,<xref rid="B123-microorganisms-08-00085" ref-type="bibr">123</xref>,<xref rid="B124-microorganisms-08-00085" ref-type="bibr">124</xref>,<xref rid="B125-microorganisms-08-00085" ref-type="bibr">125</xref>] and rarely with the death of the patient [<xref rid="B126-microorganisms-08-00085" ref-type="bibr">126</xref>]. The combined treatment MQ and mirtazapine was administered to HIV-positive patients, leading to a failure because of premature death and not always due to the PML itself [<xref rid="B127-microorganisms-08-00085" ref-type="bibr">127</xref>,<xref rid="B128-microorganisms-08-00085" ref-type="bibr">128</xref>].</p><p>One randomized study was conducted with HIV-positive and HIV-negative patients, comparing the efficacy of the standard of care normally used to treat PML to the standard of care supplemented with MQ. This study ended prematurely because of a lack of significant differences between the two groups [<xref rid="B129-microorganisms-08-00085" ref-type="bibr">129</xref>].</p></sec><sec id="sec3dot2dot2-microorganisms-08-00085"><title>3.2.2. Mefloquine and Other Viruses</title><p>A study on the antiviral effect of MQ on IAV was performed by Marois et al. MQ showed different grades of efficacy, depending on the viral strain and ranging from partial inhibition of replication to total ineffectiveness [<xref rid="B70-microorganisms-08-00085" ref-type="bibr">70</xref>].</p><p>More recently, the effect of MQ on some emerging viruses was studied. MQ was tested for the first time against the Zika virus (ZIKV) in 2016, showing different reductions in infection rate, depending on the cell model used, and different cytotoxicities, thus making it difficult to draw a conclusion [<xref rid="B130-microorganisms-08-00085" ref-type="bibr">130</xref>]. Balasubramanian et al. confirmed the in vitro effect of MQ on ZIKV infection and evaluated it on DENV, performing several in vitro assays [<xref rid="B131-microorganisms-08-00085" ref-type="bibr">131</xref>]. Sun et al. performed an in vitro screening of 795 fixed-dose drug combinations of three molecules, choosing those able to block more than 90% EBOV-like particle entry into HeLa cells. One of the three best combinations was composed of MQ with toremifene (an antagonist of estrogen receptors) and the antifungal posaconazole, whose activity was confirmed by dose-response experiments in Vero cells infected with EBOV [<xref rid="B132-microorganisms-08-00085" ref-type="bibr">132</xref>].</p><p>Although some benefits could be seen in the use of MQ as antiviral drug, its neurotoxicity should be taken into account: when it is used for malaria prophylaxis, it is known to cause serious neuropsychiatric adverse reactions, and to date, international MQ labels warn patients to discontinue it at the onset of prodromal psychiatric and neurologic symptoms [<xref rid="B133-microorganisms-08-00085" ref-type="bibr">133</xref>].</p><p>However, to date, to the best of our knowledge, there are no systematic studies concerning neurotoxic manifestations of MQ, when used ad antiviral drug, and not for the antimalarial prophylaxis. It could be speculated that in some conditions the benefit:risk ratio would look more favorable than for MQ used for malaria chemoprophylaxis.</p></sec></sec><sec id="sec3dot3-microorganisms-08-00085"><title>3.3. Halofantrine and Lumefantrine</title><p>While good results were obtained using quinine sulfate and MQ as antivirals, the same cannot be stated for halofantrine and lumefantrine, which failed in the inhibition of viral replication, based on the few studies conducted to date. Mazzon and colleagues, performing an in vitro screen of ~2500 compounds, were able to describe inhibition activity of halofantrine on Semliki Forest virus (SFV) and DENV-2, but, due to the low selectivity index of the drug, further investigations were not conducted [<xref rid="B134-microorganisms-08-00085" ref-type="bibr">134</xref>].</p><p>Lumefantrine has been tested only in a commercial combination with artemether, known as CoArtem<sup>®</sup>, as previously described in the paragraph about ART derivatives.</p></sec></sec><sec id="sec4-microorganisms-08-00085"><title>4. Aminoquinolines</title><sec id="sec4dot1-microorganisms-08-00085"><title>4.1. Chloroquine and Hydroxychloroquine and Emerging Viruses</title><p>Chloroquine (CQ) is an aminoquinoline known since 1934. It was synthesized to be used as an antimalarial drug, but its properties and mechanism of action encouraged its use for the treatment of different diseases. Currently, CQ and its hydroxy-analog hydroxychloroquine (hydroxyCQ) cannot be used as antimalarial drugs in wide areas where the resistance of malaria parasites emerged. They are commonly used for connective tissue disorders, such as rheumatoid arthritis. Due to low toxicity and cost, high tolerability and immunomodulatory properties, CQ and hydroxyCQ have also been proposed for use against viral infections. Even if their specific mechanisms in individual diseases are not clear, it is well assessed that the antiviral activities of the aminoquinoline take advantage of their strong anti-inflammatory activity. The major proposed mechanisms of actions of CQ analogs which are suggested to influence the anti-viral activity are, among the others: the inhibition of cytokine production and release by T cells: IL-1, 2, 6, or 18, tumor necrosis factor TNF-α and IFN-γ, reduced levels of chemokines CCL2 and CXCL10, inhibition of micro-RNA expression, decreased TH17-related cytokines, decreased DNA, RNA and protein synthesis in thymocytes (reviewed in [<xref rid="B135-microorganisms-08-00085" ref-type="bibr">135</xref>]).</p><p>The in vitro antiviral effect of CQ was first reported approximately 40 years ago [<xref rid="B136-microorganisms-08-00085" ref-type="bibr">136</xref>,<xref rid="B137-microorganisms-08-00085" ref-type="bibr">137</xref>], and since that time, its use as an antiviral drug has been extensively discussed. In particular, CQ/hydroxyCQ have been used for the treatment of emerging chikungunya virus (CHIKV) infection, recently causing numerous outbreaks in the world. Khan et al. showed that the treatment of infected Vero cells with different micromolar concentrations of CQ reduced virus yield and viral RNA copy number [<xref rid="B138-microorganisms-08-00085" ref-type="bibr">138</xref>]. De Lamballerie and colleagues confirmed the inhibition of CHIKV replication in Vero-E6 cells using CQ. The efficacy of CQ was inversely related to the concentration of the viral inoculum used, an unfavorable observation, considering the high viremia measured at the acute stage of CHIKV infection (up to 10<sup>10</sup> virus copies/mL serum) [<xref rid="B37-microorganisms-08-00085" ref-type="bibr">37</xref>]. Sourisseau and colleagues treated HeLa cells with CQ, obtaining a potent inhibition of CHIKV replication and its relative cytopathic effects [<xref rid="B139-microorganisms-08-00085" ref-type="bibr">139</xref>].</p><p>A double-blind placebo-controlled trial was designed to evaluate the efficacy and safety of CQ for the treatment of CHIKV infection in 2006 in French Reunion Island (Indian Ocean). No significant difference was observed between the CQ and placebo groups, either in the mean duration of febrile arthralgia or in the rate of viremia decrease [<xref rid="B37-microorganisms-08-00085" ref-type="bibr">37</xref>]. However, the number of patients included in the study was too small to draw definitive conclusions regarding the efficacy of CQ treatment (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>) [<xref rid="B37-microorganisms-08-00085" ref-type="bibr">37</xref>]. Aminoquinolines were proposed for the treatment of other viral infections, such as ZIKV. In 2017, it was demonstrated that CQ and AQ exerted anti-ZIKV activity in Vero cells, with low micromolar IC<sub>50</sub>s [<xref rid="B140-microorganisms-08-00085" ref-type="bibr">140</xref>]. These results were in agreement with the decreasing number of ZIKV-infected cells after CQ treatment. Additionally, CQ protected the cells from further ZIKV infection, as measured by cell viability at noncytotoxic concentrations [<xref rid="B141-microorganisms-08-00085" ref-type="bibr">141</xref>].</p><p>The activity of CQ has also been indirectly demonstrated against DENV infection. The results obtained by Kleber and colleagues showed that CQ suppressed TNF-α and IFN-γ production, and it was hypothesized that CQ might be used to treat patients suspected of having dengue disease, avoiding the more severe form of dengue hemorrhagic fever and/or shock. A clinical trial was also established to verify the effect of CQ versus placebo in DENV-infected patients in Brazil. CQ promoted a reduction in the intensity of pain and an improvement in the well-being of patients with DENV infection but did not alter the duration of the disease or the intensity and days of fever (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>) [<xref rid="B36-microorganisms-08-00085" ref-type="bibr">36</xref>].</p><p>To study the effects of CQ against EBOV, a group led by Dowall conducted an in vitro investigation using the human cell line MRC-5 and in vivo studies with the well-characterized guinea pig model [<xref rid="B142-microorganisms-08-00085" ref-type="bibr">142</xref>]. They were able to demonstrate that CQ reduced EBOV replication in MRC-5 cells. In contrast, the administration of CQ to 12 Guinea pigs did not protect the infected animals against the Ebola disease [<xref rid="B142-microorganisms-08-00085" ref-type="bibr">142</xref>]. Madrid and colleagues suggested that CQ could interfere with the late stages of EBOV replication and assembly [<xref rid="B143-microorganisms-08-00085" ref-type="bibr">143</xref>]. Despite these positive in vitro results, the clinical trials were sometimes conflicting. For this reason, later, the literature was reviewed to clarify the efficacy of CQ in the treatment of filovirus infection [<xref rid="B144-microorganisms-08-00085" ref-type="bibr">144</xref>]. It was concluded that the efficacy of CQ against the viruses belonging to this family was dependent on the CQ plasma concentrations, which must be sustained in patients until the clearance of the viremia [<xref rid="B144-microorganisms-08-00085" ref-type="bibr">144</xref>].</p><p>CQ was shown to inhibit the replication and spread of coronavirus (CoV) in vitro and to prevent infection with CoV in newborn mice. Since the suppressive effect of CQ was also present when the cells were treated before the infection, a prophylactic advantage of CQ use was suggested [<xref rid="B145-microorganisms-08-00085" ref-type="bibr">145</xref>,<xref rid="B146-microorganisms-08-00085" ref-type="bibr">146</xref>,<xref rid="B147-microorganisms-08-00085" ref-type="bibr">147</xref>].</p></sec><sec id="sec4dot2-microorganisms-08-00085"><title>4.2. Chloroquine and Hydroxychloroquine and HCV</title><p>CQ and its analogs have effects against HCV. In particular, the treatment of JFH-1 or Huh-7 cells with CQ reduced HCV entry, replication, and infection in a dose-dependent manner [<xref rid="B148-microorganisms-08-00085" ref-type="bibr">148</xref>,<xref rid="B149-microorganisms-08-00085" ref-type="bibr">149</xref>,<xref rid="B150-microorganisms-08-00085" ref-type="bibr">150</xref>]. Furthermore, CQ, in combination with IFN-α, prevented the replication of HCV and enhanced the antiviral effect of IFN-α [<xref rid="B149-microorganisms-08-00085" ref-type="bibr">149</xref>].</p><p>In this regard, two phase I/II clinical trials were initiated to verify the efficacy of the combination treatment of hydroxyCQ and ribavirin, but no results were posted due to limited recruitment.</p></sec><sec id="sec4dot3-microorganisms-08-00085"><title>4.3. Chloroquine and Hydroxychloroquine and HIV</title><p>The anti-HIV-1 and anti-HIV-2 activities of CQ and its analogs were tested in vitro and in vivo. The first report about the in vitro use of CQ as an anti-HIV-1 agent was published in 1990 by Tsai et al., which showed the suppressive effects of CQ on the replication of HIV-1 in a T cell line [<xref rid="B151-microorganisms-08-00085" ref-type="bibr">151</xref>]. A few years later, Sperber and colleagues confirmed these results, showing the ability of CQ and hydroxyCQ to inhibit HIV-1 replication not only in T cells but also in monocytes [<xref rid="B152-microorganisms-08-00085" ref-type="bibr">152</xref>,<xref rid="B153-microorganisms-08-00085" ref-type="bibr">153</xref>]. Subsequently, the same group demonstrated the CQ and hydroxyCQ anti-HIV-1 and anti-HIV-2 in vitro effects at concentrations that are clinically achievable [<xref rid="B154-microorganisms-08-00085" ref-type="bibr">154</xref>]. CQ had an additive effect against HIV-1 when used in combination with other antiretroviral agents [<xref rid="B155-microorganisms-08-00085" ref-type="bibr">155</xref>,<xref rid="B156-microorganisms-08-00085" ref-type="bibr">156</xref>]. Naarding et al. demonstrated that CQ reduced HIV-1 transmission to and replication in CD4 + T-lymphocytes [<xref rid="B157-microorganisms-08-00085" ref-type="bibr">157</xref>]. Similarly, Martinson et al. observed that CQ had a preventive role in HIV infection, reducing CD8 + T cell activation upon HIV replication [<xref rid="B158-microorganisms-08-00085" ref-type="bibr">158</xref>].</p><p>The antiviral activity of hydroxyCQ was demonstrated in vivo by several clinical trials. The somministration of hydroxyCQ was able to reduce the amounts of plasma HIV-1 RNA and IL-6 in patients treated for eight weeks compared to those of the placebo group [<xref rid="B39-microorganisms-08-00085" ref-type="bibr">39</xref>]. During a second clinical trial, hydroxyCQ was shown to reduce the HIV-1 RNA plasma level, although at a lower level than the antiviral zidovudine [<xref rid="B40-microorganisms-08-00085" ref-type="bibr">40</xref>]. In contrast, the results published in 2012 by Paton and colleagues showed negative results, with an increase in viral load and a decrease in CD4 number [<xref rid="B41-microorganisms-08-00085" ref-type="bibr">41</xref>].</p><p>Another double-blind, randomized placebo-controlled trial testing the effects of CQ in 13 chronically HIV-infected persons was conducted in Minnesota. The results showed that the administration of CQ during chronic HIV infection resulted in decreased immune activation, but no data regarding HIV status were reported [<xref rid="B43-microorganisms-08-00085" ref-type="bibr">43</xref>].</p><p>Very recently, the AIDS Clinical Trials Group A5258 was completed. It was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy and 37 participants on antiretroviral therapy. CQ modestly reduced immune activation in antiretroviral therapy-treated HIV-infected participants [<xref rid="B42-microorganisms-08-00085" ref-type="bibr">42</xref>].</p><p>Finally, the recruitment of 1499 patients was concluded a few months ago in a randomized, controlled, open-label, phase III trial of the standard of care with CQ prophylaxis compared to no prophylaxis in HIV-positive patients in Malawi (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>) [<xref rid="B44-microorganisms-08-00085" ref-type="bibr">44</xref>,<xref rid="B45-microorganisms-08-00085" ref-type="bibr">45</xref>].</p><sec><title>Chloroquine and Hydroxychloroquine and Other RNA Viruses</title><p>CQ was shown to inhibit the in vitro replication of H1N1 and H3N2 IAV strains [<xref rid="B159-microorganisms-08-00085" ref-type="bibr">159</xref>]. A phase II clinical trial aiming to verify the effect of CQ compared to that of placebo on IAV was started in Singapore in 2005, and 1516 patients were recruited. However, CQ was not shown to prevent infection with IAV (<xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>) [<xref rid="B38-microorganisms-08-00085" ref-type="bibr">38</xref>].</p><p>CQ had inhibitory effects on the entry and replication of enterovirus (EV)-A71 in cell-based systems [<xref rid="B160-microorganisms-08-00085" ref-type="bibr">160</xref>]. Yong and colleagues studied the efficacy of CQ against several EV serotypes and evaluated its therapeutic capacity in vitro in RD cells and in vivo in a murine model [<xref rid="B161-microorganisms-08-00085" ref-type="bibr">161</xref>]. They demonstrated the potential of CQ as an antiviral in the treatment of hand, foot, and mouth disease caused by EV infection. The positive results obtained in the murine model of infection were indicative of the fact that CQ may mitigate the disease severity in mammals [<xref rid="B161-microorganisms-08-00085" ref-type="bibr">161</xref>].</p></sec></sec><sec id="sec4dot4-microorganisms-08-00085"><title>4.4. Amodiaquine and Emerging Viruses</title><p>Amodiaquine (AQ) was originally developed and has been widely used for the treatment of malaria. However, subsequent studies revealed that it was active against a wide range of human pathogens, including several viruses. In a study published in 2014, it was investigated whether quinolone derivatives could inhibit the replication of DENV [<xref rid="B162-microorganisms-08-00085" ref-type="bibr">162</xref>]. The time-course analysis suggested that AQ was stable and that it reproducibly inhibited DENV infectivity. The data also showed that viral entry and internalization were partially inhibited by the drug, but the major effect occurred at a later stage of the viral life cycle [<xref rid="B162-microorganisms-08-00085" ref-type="bibr">162</xref>].</p><p>It is known that AQ inhibits EBOV replication in vivo [<xref rid="B58-microorganisms-08-00085" ref-type="bibr">58</xref>]. A recent study demonstrated that AQ was active against severe fever with thrombocytopenia syndrome (SFTS) caused by SFTS virus (SFTSV) [<xref rid="B163-microorganisms-08-00085" ref-type="bibr">163</xref>].</p></sec><sec id="sec4dot5-microorganisms-08-00085"><title>4.5. Primaquine</title><p>Primaquine was tested as an antiviral on primary chicken embryo cells (CECs) infected by Newcastle disease virus [<xref rid="B164-microorganisms-08-00085" ref-type="bibr">164</xref>]. It was demonstrated that primaquine had an effect on the accumulation of viral hemagglutinin on the cell surface. In addition, primaquine inhibited protein synthesis in virus-infected cells [<xref rid="B164-microorganisms-08-00085" ref-type="bibr">164</xref>].</p></sec></sec><sec id="sec5-microorganisms-08-00085"><title>5. Other Antimalarial Drugs</title><sec id="sec5dot1-microorganisms-08-00085"><title>5.1. Atovaquone</title><p>Atovaquone, a naphthoquinone antimalarial drug often used in pregnant women, is a ubiquinone (coenzyme Q) analog that inhibits mitochondrial cytochrome complex III (bc1 complex). It is also able to deplete the intracellular nucleotide pools by inhibiting dihydroorotate dehydrogenase, an enzyme for de novo pyrimidine synthesis [<xref rid="B165-microorganisms-08-00085" ref-type="bibr">165</xref>]. In 2019, one published work reported the in vitro antiviral action of atovaquone against CHIKV. Low micromolar doses inhibited the number of infected cells, as evaluated by high-content fluorescence microscopy. The result was then confirmed by the reduction in CHIKV virions in different cells by plaque assay [<xref rid="B164-microorganisms-08-00085" ref-type="bibr">164</xref>]. In the same paper, Kottkamp and colleagues evaluated the ability of atovaquone to reduce the infectivity of both a Brazilian and a Ugandan strain of ZIKV by immunostaining the envelope after treatment and infection and subsequent plaque assay in different cells. These data were further confirmed ex vivo in a human placenta tissue model, with a dose-dependent reduction in infection and virion production by the Ugandan strain [<xref rid="B166-microorganisms-08-00085" ref-type="bibr">166</xref>].</p></sec><sec id="sec5dot2-microorganisms-08-00085"><title>5.2. Antimicrobial Drugs</title><p>Antibiotic drugs, such as doxycycline and sulfonamides, are widely used in the chemoprophylaxis of malaria in all malaria areas [<xref rid="B167-microorganisms-08-00085" ref-type="bibr">167</xref>]. It has been reported that these therapies could have activities beyond antimalarial activity, also against viral infectious agents. Surprisingly, in many cases, the administration of antibiotics alone or in combination with other antiviral agents showed significant antiviral activities against different types of viral infections [<xref rid="B168-microorganisms-08-00085" ref-type="bibr">168</xref>,<xref rid="B169-microorganisms-08-00085" ref-type="bibr">169</xref>,<xref rid="B170-microorganisms-08-00085" ref-type="bibr">170</xref>,<xref rid="B171-microorganisms-08-00085" ref-type="bibr">171</xref>]. Despite this evidence, the antiviral mechanisms of action have not been completely investigated.</p><sec id="sec5dot2dot1-microorganisms-08-00085"><title>5.2.1. Doxycycline</title><p>Doxycycline (DOX) is a semisynthetic tetracycline antibiotic that prevents bacterial protein synthesis by acting on ribosomes (30S subunit) [<xref rid="B167-microorganisms-08-00085" ref-type="bibr">167</xref>,<xref rid="B172-microorganisms-08-00085" ref-type="bibr">172</xref>,<xref rid="B173-microorganisms-08-00085" ref-type="bibr">173</xref>,<xref rid="B174-microorganisms-08-00085" ref-type="bibr">174</xref>,<xref rid="B175-microorganisms-08-00085" ref-type="bibr">175</xref>]. DOX, widely used alone or in combination with quinine for chemoprophylaxis in CQ-resistant <italic>P. falciparum</italic> cases of malaria [<xref rid="B176-microorganisms-08-00085" ref-type="bibr">176</xref>], has been shown to exert inhibitory effects against different microbial infections.</p><p>DOX significantly inhibited the proliferation of a panel of HPV-positive cervical cancer cell lines, also inducing apoptosis of cervical cancer cells in a time- and dose-dependent manner [<xref rid="B177-microorganisms-08-00085" ref-type="bibr">177</xref>].</p><p>Concerning emerging infections, in a recent work, researchers tried to identify candidate antibiotics that can block the function of DENV viral envelope proteins to prevent viral entry. Using an innovative visual screening approach coupling computational studies and biologic assays on ten nontoxic candidates, they suggested that DOX significantly inhibited plaque formation, demonstrating an inhibitory effect on DENV propagation [<xref rid="B178-microorganisms-08-00085" ref-type="bibr">178</xref>]. This result was confirmed by Rothan and colleagues, who evaluated the replication rate of DENV in an in vitro model of infected cells. They reported that DOX inhibited DENV replication in vitro by reducing viral protease activity and entry into host cells [<xref rid="B168-microorganisms-08-00085" ref-type="bibr">168</xref>]. The same research group determined the inhibitory effects of DOX against CHIKV as well as its possible effect on the virus life cycle in Vero cells when the virus and the drug were administered concurrently to the cells. Computational studies indicated that DOX might be a noncompetitive inhibitor of CHIKV protease. This hypothesis was confirmed by in vitro experiments demonstrating that the effect of DOX was directed more toward viral entry than toward viral replication [<xref rid="B169-microorganisms-08-00085" ref-type="bibr">169</xref>]. Furthermore, the inhibitory effect of DOX on the replication of vesicular stomatitis virus (VSV) in different stably infected cell lines was reported [<xref rid="B170-microorganisms-08-00085" ref-type="bibr">170</xref>]. The results showed significant inhibition of the replication of VSV in a dose-dependent but not cell-type dependent manner, suggesting that DOX exerted its antiviral activity at the early-mid stage of VSV infection [<xref rid="B170-microorganisms-08-00085" ref-type="bibr">170</xref>]. These results indicated a different mode of action of DOX against VSV than that against DENV and CHIKV, suggesting that the antiviral activity of DOX could be dependent on the virus species. Finally, only an in vivo study was published on IAV. Treatment with DOX attenuated acute lung injury in mice infected with a virulent IAV H3N2 strain, with no effects on virus titers, suggesting that the antibiotic treatment was able to alleviate severe influenza pneumonia symptoms [<xref rid="B171-microorganisms-08-00085" ref-type="bibr">171</xref>]. It is, therefore, possible to conclude that despite the role of DOX as a potential antiviral agent in vitro, the mechanisms of viral replication inhibition and the targeted virus species have yet to be clarified. Clinical trials confirming in vitro observations are needed.</p></sec><sec id="sec5dot2dot2-microorganisms-08-00085"><title>5.2.2. Sulfonamides</title><p>Sulfonamides constitute an important class of drugs containing many types of pharmacological agents with broad-spectrum bacteriostatic activity. Sulfonamides interrupt the synthesis of folic acid, interfering with the dihydropteroate synthase and dihydrofolate reductase enzymes of bacteria (and protozoa) and inhibiting bacterial growth [<xref rid="B179-microorganisms-08-00085" ref-type="bibr">179</xref>,<xref rid="B180-microorganisms-08-00085" ref-type="bibr">180</xref>]. The sulfadoxine-pyrimethamine combination is used in some settings for the treatment of uncomplicated malaria in pregnant women, and it is the only drug currently recommended for intermittent preventive therapy during pregnancy [<xref rid="B181-microorganisms-08-00085" ref-type="bibr">181</xref>]. A study investigated the effect of this combination on HIV replication. Experiments were conducted in vitro using peripheral blood mononuclear cells, MT-2 cells, MT-4 cells, and a latently infected cell line named U1. The results showed that the sulfadoxine-pyrimethamine combination combined with antiretroviral therapy significantly enhanced HIV replication in MT-2 cells, while it inhibited HIV replication in peripheral blood mononuclear cells [<xref rid="B23-microorganisms-08-00085" ref-type="bibr">23</xref>]. Moreover, recent studies have demonstrated that sulfonamides can act on latent herpesviruses, such as EBV and Kaposi sarcoma herpesvirus (KSHV) [<xref rid="B182-microorganisms-08-00085" ref-type="bibr">182</xref>,<xref rid="B183-microorganisms-08-00085" ref-type="bibr">183</xref>]. Furthermore, a work conducted by Angius and colleagues reported that sulfonamide antibiotics suppressed the KSHV latent state in permanently infected lymphoma cells [<xref rid="B183-microorganisms-08-00085" ref-type="bibr">183</xref>]. This result suggested that sulfonamides might play a potential role in clearing KSHV-infected lymphoma cells. Since conventional antiherpes drugs are able to slightly suppress viral replication in the lytic phase but do not clear the latent state, the finding of potential new small molecules, such as sulfonamides drugs, could initiate a promising program of studies on both oncogenic and degenerative diseases, in which herpesvirus latency is suspected to be involved [<xref rid="B184-microorganisms-08-00085" ref-type="bibr">184</xref>,<xref rid="B185-microorganisms-08-00085" ref-type="bibr">185</xref>,<xref rid="B186-microorganisms-08-00085" ref-type="bibr">186</xref>].</p></sec></sec></sec><sec sec-type="conclusions" id="sec6-microorganisms-08-00085"><title>6. Conclusions</title><p>Antimalarial drugs have been widely tested against a large number of viruses, especially in vitro, with variable outcomes (<xref rid="microorganisms-08-00085-t003" ref-type="table">Table 3</xref>). Among the ART derivates, some showed strong activities against viruses, such as AS against HCMV, ART, and AS against HBV and HCV, and AS against HPV and HPyV, whereas data regarding the activity against HIV are uncertain.</p><p>Among the aryl-aminoalcohols, the use of MQ in the treatment of JCPyV infection has been extensive, although with contradictory outcomes. Among the aminoquinolines, both CQ and hydroxyCQ showed promising results in reducing the replication of some emerging viruses, such as DENV and ZIKV.</p><p>Emerging infections have also been targeted by antibacterial drugs, such as DOX. However, the successful use of antimalarial drugs in vitro did not always lead to a satisfactory outcome in their clinical application (<xref rid="microorganisms-08-00085-t004" ref-type="table">Table 4</xref>).</p><p>Nevertheless, some drugs have already been used in several clinical trials, as summarized in <xref rid="microorganisms-08-00085-t001" ref-type="table">Table 1</xref>. Most of them regard the use of antimalarial drugs against HIV infection, but some of them failed, and for others, the final results are not available. Although these outcomes can seem discouraging, at least four clinical trials deserve attention: The one on the use of AS against HCMV, with particular regard to the drug-resistant strains, the one targeting CHIKV with CQ, and the other two very innovative and ongoing trials on the use of AS against HPV for the treatment of anal and cervical intraepithelial high-grade neoplasia.</p><p>Based on these observations, we can state that the use of antimalarial drugs might be useful, especially in cases of antiviral resistance and in light of the emergence of many viruses against which effective drugs are not available.</p></sec></body><back><notes><title>Author Contributions</title><p>Conceptualization, S.D. (Sarah D’Alessandro) and S.D. (Serena Delbue); writing—original draft preparation, S.D. (Sarah D’Alessandro), D.S., L.S., F.P.; writing—review and editing, S.D. (Sarah D’Alessandro), D.S., L.S., F.P., S.D. (Serena Delbue), D.P.I.; supervision, S.D. (Serena Delbue), P.F.; funding acquisition, S.D. (Sarah D’Alessandro). All authors have read and agreed to the published version of the manuscript.</p></notes><notes><title>Funding</title><p>This work was partially supported by “Fondazione Cariplo” (grant number 2017–0846) to S.A.</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>The authors declare no conflict of interest.</p></notes><glossary><title>Abbreviations</title><array orientation="portrait"><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">AQ</td><td align="left" valign="middle" rowspan="1" colspan="1">Amodiaquine</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ART</td><td align="left" valign="middle" rowspan="1" colspan="1">Artemisinin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">AS</td><td align="left" valign="middle" rowspan="1" colspan="1">Artesunate</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CHIKV</td><td align="left" valign="middle" rowspan="1" colspan="1">Chikungunya virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">CQ</td><td align="left" valign="middle" rowspan="1" colspan="1">Chloroquine</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DENV</td><td align="left" valign="middle" rowspan="1" colspan="1">Dengue virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">DHA</td><td align="left" valign="middle" rowspan="1" colspan="1">Dihydroartemisinin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EC<sub>50</sub>s</td><td align="left" valign="middle" rowspan="1" colspan="1">Effective concentrations</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">EBV</td><td align="left" valign="middle" rowspan="1" colspan="1">Epstein-Barr virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HBV</td><td align="left" valign="middle" rowspan="1" colspan="1">Hepatitis B virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HCMV</td><td align="left" valign="middle" rowspan="1" colspan="1">Human cytomegalovirus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HCV</td><td align="left" valign="middle" rowspan="1" colspan="1">Hepatitis C virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">HPV</td><td align="left" valign="middle" rowspan="1" colspan="1">Human papillomavirus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">hydroxyCQ</td><td align="left" valign="middle" rowspan="1" colspan="1">hydroxychloroquine</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">IL</td><td align="left" valign="middle" rowspan="1" colspan="1">Interleukin</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">INF</td><td align="left" valign="middle" rowspan="1" colspan="1">Interferon</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">KSHV</td><td align="left" valign="middle" rowspan="1" colspan="1">Kaposi sarcoma herpesvirus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">MQ</td><td align="left" valign="middle" rowspan="1" colspan="1">Mefloquine</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">RCMV</td><td align="left" valign="middle" rowspan="1" colspan="1">Rat cytomegalovirus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">TNF</td><td align="left" valign="middle" rowspan="1" colspan="1">Tumor necrosis factor</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">VSV</td><td align="left" valign="middle" rowspan="1" colspan="1">Vesicular stomatitis virus</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">ZIKV</td><td align="left" valign="middle" rowspan="1" colspan="1">Zika virus</td></tr></tbody></array></glossary><ref-list><title>References</title><ref id="B1-microorganisms-08-00085"><label>1.</label><element-citation publication-type="book"><person-group 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align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Virus Species</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drug</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Trial Number/Reference</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Outcome</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Herpesviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HCMV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT00284687</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">No results</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Papillomaviridae</italic></td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HPV</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03100045</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">Ongoing</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT04098744</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">Ongoing</td></tr><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Flaviviridae</italic></td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HCV</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01833845</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">Terminated due to failure to recruit subjects</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01272310</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">Unknown</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DENV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT00849602</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reduction in pain but not in length of disease [<xref rid="B36-microorganisms-08-00085" ref-type="bibr">36</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CHIKV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT003913131</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No difference between CQ- and placebo-treated groups [<xref rid="B37-microorganisms-08-00085" ref-type="bibr">37</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Orthomyxoviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IAV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01078779</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No prevention of IAV infection [<xref rid="B38-microorganisms-08-00085" ref-type="bibr">38</xref>]</td></tr><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Retroviridae</italic></td><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HIV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B39-microorganisms-08-00085" ref-type="bibr">39</xref>,<xref rid="B40-microorganisms-08-00085" ref-type="bibr">40</xref>]</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reduction in HIV-1 RNA load in plasma</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ISRCTN30019040</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increased HIV-1 replication and decreased CD4 numbers [<xref rid="B41-microorganisms-08-00085" ref-type="bibr">41</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT00819390</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Modest reduction in immune activation [<xref rid="B42-microorganisms-08-00085" ref-type="bibr">42</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02004314</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Patients did not experience any improvement after CQ treatment [<xref rid="B43-microorganisms-08-00085" ref-type="bibr">43</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01650558</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Terminated, awaiting results [<xref rid="B44-microorganisms-08-00085" ref-type="bibr">44</xref>,<xref rid="B45-microorganisms-08-00085" ref-type="bibr">45</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="microorganisms-08-00085-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">microorganisms-08-00085-t002_Table 2</object-id><label>Table 2</label><caption><p>Clinical studies assessing the efficacy of Mefloquine (MQ) treatment and its combinations in JCPyV-infected progressive multifocal leukoencephalopathy (PML) patients.</p></caption><table frame="hsides" rules="groups"><thead><tr><th colspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Case Reports</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HIV Status</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Treatment</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Outcome</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="11" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HIV negative </td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Mefloquine</td><td align="center" valign="middle" rowspan="1" colspan="1">No PML progression</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B72-microorganisms-08-00085" ref-type="bibr">72</xref>,<xref rid="B73-microorganisms-08-00085" ref-type="bibr">73</xref>,<xref rid="B74-microorganisms-08-00085" ref-type="bibr">74</xref>,<xref rid="B77-microorganisms-08-00085" ref-type="bibr">77</xref>,<xref rid="B78-microorganisms-08-00085" ref-type="bibr">78</xref>,<xref rid="B79-microorganisms-08-00085" ref-type="bibr">79</xref>,<xref rid="B81-microorganisms-08-00085" ref-type="bibr">81</xref>,<xref rid="B82-microorganisms-08-00085" ref-type="bibr">82</xref>,<xref rid="B83-microorganisms-08-00085" ref-type="bibr">83</xref>,<xref rid="B84-microorganisms-08-00085" ref-type="bibr">84</xref>,<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fatal outcome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>,<xref rid="B76-microorganisms-08-00085" ref-type="bibr">76</xref>,<xref rid="B80-microorganisms-08-00085" ref-type="bibr">80</xref>,<xref rid="B85-microorganisms-08-00085" ref-type="bibr">85</xref>,<xref rid="B88-microorganisms-08-00085" ref-type="bibr">88</xref>]</td></tr><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Mefloquine + mirtazapine</td><td align="center" valign="middle" rowspan="1" colspan="1">PML resolution with claimed effects</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B89-microorganisms-08-00085" ref-type="bibr">89</xref>,<xref rid="B90-microorganisms-08-00085" ref-type="bibr">90</xref>,<xref rid="B91-microorganisms-08-00085" ref-type="bibr">91</xref>,<xref rid="B92-microorganisms-08-00085" ref-type="bibr">92</xref>,<xref rid="B93-microorganisms-08-00085" ref-type="bibr">93</xref>,<xref rid="B94-microorganisms-08-00085" ref-type="bibr">94</xref>,<xref rid="B95-microorganisms-08-00085" ref-type="bibr">95</xref>,<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B97-microorganisms-08-00085" ref-type="bibr">97</xref>,<xref rid="B98-microorganisms-08-00085" ref-type="bibr">98</xref>,<xref rid="B99-microorganisms-08-00085" ref-type="bibr">99</xref>,<xref rid="B100-microorganisms-08-00085" ref-type="bibr">100</xref>,<xref rid="B101-microorganisms-08-00085" ref-type="bibr">101</xref>,<xref rid="B102-microorganisms-08-00085" ref-type="bibr">102</xref>,<xref rid="B103-microorganisms-08-00085" ref-type="bibr">103</xref>,<xref rid="B104-microorganisms-08-00085" ref-type="bibr">104</xref>,<xref rid="B105-microorganisms-08-00085" ref-type="bibr">105</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PML resolution due to other factors</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B106-microorganisms-08-00085" ref-type="bibr">106</xref>,<xref rid="B107-microorganisms-08-00085" ref-type="bibr">107</xref>,<xref rid="B108-microorganisms-08-00085" ref-type="bibr">108</xref>,<xref rid="B109-microorganisms-08-00085" ref-type="bibr">109</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Fatal outcome</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B110-microorganisms-08-00085" ref-type="bibr">110</xref>,<xref rid="B111-microorganisms-08-00085" ref-type="bibr">111</xref>,<xref rid="B112-microorganisms-08-00085" ref-type="bibr">112</xref>,<xref rid="B113-microorganisms-08-00085" ref-type="bibr">113</xref>,<xref rid="B114-microorganisms-08-00085" ref-type="bibr">114</xref>,<xref rid="B115-microorganisms-08-00085" ref-type="bibr">115</xref>,<xref rid="B116-microorganisms-08-00085" ref-type="bibr">116</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Therapy suspension due to side effects</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B117-microorganisms-08-00085" ref-type="bibr">117</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Mefloquine + mirtazapine + third partner drug</td><td align="center" valign="middle" rowspan="1" colspan="1">PML resolution</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B118-microorganisms-08-00085" ref-type="bibr">118</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fatal outcome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B119-microorganisms-08-00085" ref-type="bibr">119</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine + risperidone</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fatal outcome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine + risperidone + cytarabine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PML resolution</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B120-microorganisms-08-00085" ref-type="bibr">120</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine + cidofovir</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PML resolution due to other factors</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B121-microorganisms-08-00085" ref-type="bibr">121</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HIV positive </td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Mefloquine</td><td align="center" valign="middle" rowspan="1" colspan="1">No PML progression</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B122-microorganisms-08-00085" ref-type="bibr">122</xref>,<xref rid="B123-microorganisms-08-00085" ref-type="bibr">123</xref>,<xref rid="B124-microorganisms-08-00085" ref-type="bibr">124</xref>,<xref rid="B125-microorganisms-08-00085" ref-type="bibr">125</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fatal outcome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B126-microorganisms-08-00085" ref-type="bibr">126</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine + mirtazapine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Premature fatal outcome</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B127-microorganisms-08-00085" ref-type="bibr">127</xref>,<xref rid="B128-microorganisms-08-00085" ref-type="bibr">128</xref>]</td></tr><tr><td colspan="4" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Clinical Trial</bold></td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HIV negative versus HIV positive patients</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Standard of care (SOC) versus SOC + mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lack of differences: study ended prematurely</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B129-microorganisms-08-00085" ref-type="bibr">129</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="microorganisms-08-00085-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">microorganisms-08-00085-t003_Table 3</object-id><label>Table 3</label><caption><p>In vitro/in vivo studies for the assessment of antimalarial drug activity against viral infection.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Virus Family</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Virus Species</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drug</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type of Study (Model)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="13" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Herpesviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSV-1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Quinine sulfate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B68-microorganisms-08-00085" ref-type="bibr">68</xref>,<xref rid="B69-microorganisms-08-00085" ref-type="bibr">69</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">EBV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B50-microorganisms-08-00085" ref-type="bibr">50</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sulfonamides</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B182-microorganisms-08-00085" ref-type="bibr">182</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HCMV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B10-microorganisms-08-00085" ref-type="bibr">10</xref>,<xref rid="B11-microorganisms-08-00085" ref-type="bibr">11</xref>,<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>,<xref rid="B17-microorganisms-08-00085" ref-type="bibr">17</xref>,<xref rid="B24-microorganisms-08-00085" ref-type="bibr">24</xref>,<xref rid="B25-microorganisms-08-00085" ref-type="bibr">25</xref>,<xref rid="B26-microorganisms-08-00085" ref-type="bibr">26</xref>,<xref rid="B27-microorganisms-08-00085" ref-type="bibr">27</xref>,<xref rid="B28-microorganisms-08-00085" ref-type="bibr">28</xref>,<xref rid="B29-microorganisms-08-00085" ref-type="bibr">29</xref>,<xref rid="B30-microorganisms-08-00085" ref-type="bibr">30</xref>,<xref rid="B31-microorganisms-08-00085" ref-type="bibr">31</xref>,<xref rid="B32-microorganisms-08-00085" ref-type="bibr">32</xref>,<xref rid="B33-microorganisms-08-00085" ref-type="bibr">33</xref>,<xref rid="B34-microorganisms-08-00085" ref-type="bibr">34</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Arthemeter</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B61-microorganisms-08-00085" ref-type="bibr">61</xref>,<xref rid="B62-microorganisms-08-00085" ref-type="bibr">62</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HHV-6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B51-microorganisms-08-00085" ref-type="bibr">51</xref>,<xref rid="B53-microorganisms-08-00085" ref-type="bibr">53</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HHV-6B</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B52-microorganisms-08-00085" ref-type="bibr">52</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">KSHV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B183-microorganisms-08-00085" ref-type="bibr">183</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HSE</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo (mouse)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B35-microorganisms-08-00085" ref-type="bibr">35</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dihydroartemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B16-microorganisms-08-00085" ref-type="bibr">16</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">KSHV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sulfonamides</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B183-microorganisms-08-00085" ref-type="bibr">183</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">RCMV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo (rat)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B11-microorganisms-08-00085" ref-type="bibr">11</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Polyomaviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">BKPyV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B55-microorganisms-08-00085" ref-type="bibr">55</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">JCPyV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-microorganisms-08-00085" ref-type="bibr">54</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B71-microorganisms-08-00085" ref-type="bibr">71</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Hepadnaviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HBV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin, artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B17-microorganisms-08-00085" ref-type="bibr">17</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Papillomaviridae</italic></td><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HPV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B18-microorganisms-08-00085" ref-type="bibr">18</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dihydroartemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo (dog)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B19-microorganisms-08-00085" ref-type="bibr">19</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B177-microorganisms-08-00085" ref-type="bibr">177</xref>]</td></tr><tr><td rowspan="17" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Flaviviridae</italic></td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">BVDV(surrogate HCV)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B187-microorganisms-08-00085" ref-type="bibr">187</xref>,<xref rid="B188-microorganisms-08-00085" ref-type="bibr">188</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dihydroartemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B63-microorganisms-08-00085" ref-type="bibr">63</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HCV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B20-microorganisms-08-00085" ref-type="bibr">20</xref>,<xref rid="B21-microorganisms-08-00085" ref-type="bibr">21</xref>,<xref rid="B22-microorganisms-08-00085" ref-type="bibr">22</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B57-microorganisms-08-00085" ref-type="bibr">57</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B148-microorganisms-08-00085" ref-type="bibr">148</xref>,<xref rid="B149-microorganisms-08-00085" ref-type="bibr">149</xref>,<xref rid="B150-microorganisms-08-00085" ref-type="bibr">150</xref>]</td></tr><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">ZIKV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B130-microorganisms-08-00085" ref-type="bibr">130</xref>,<xref rid="B131-microorganisms-08-00085" ref-type="bibr">131</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B140-microorganisms-08-00085" ref-type="bibr">140</xref>,<xref rid="B141-microorganisms-08-00085" ref-type="bibr">141</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amodiaquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B140-microorganisms-08-00085" ref-type="bibr">140</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atovaquone</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B166-microorganisms-08-00085" ref-type="bibr">166</xref>]</td></tr><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">DENV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Quinine sulfate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B66-microorganisms-08-00085" ref-type="bibr">66</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B131-microorganisms-08-00085" ref-type="bibr">131</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Halofantrine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B134-microorganisms-08-00085" ref-type="bibr">134</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B168-microorganisms-08-00085" ref-type="bibr">168</xref>,<xref rid="B178-microorganisms-08-00085" ref-type="bibr">178</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amodiaquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B162-microorganisms-08-00085" ref-type="bibr">162</xref>]</td></tr><tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">CHIKV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B169-microorganisms-08-00085" ref-type="bibr">169</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B37-microorganisms-08-00085" ref-type="bibr">37</xref>,<xref rid="B138-microorganisms-08-00085" ref-type="bibr">138</xref>,<xref rid="B139-microorganisms-08-00085" ref-type="bibr">139</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atovaquone</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B166-microorganisms-08-00085" ref-type="bibr">166</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Togaviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SFV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Halofantrine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B134-microorganisms-08-00085" ref-type="bibr">134</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Rhabdoviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VSV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B170-microorganisms-08-00085" ref-type="bibr">170</xref>]</td></tr><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Orthomyxoviridae</italic></td><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">IAV</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Quinine sulfate</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B70-microorganisms-08-00085" ref-type="bibr">70</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vivo (mouse)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B67-microorganisms-08-00085" ref-type="bibr">67</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B70-microorganisms-08-00085" ref-type="bibr">70</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo (mouse)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B171-microorganisms-08-00085" ref-type="bibr">171</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B159-microorganisms-08-00085" ref-type="bibr">159</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Coronaviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CoV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B145-microorganisms-08-00085" ref-type="bibr">145</xref>,<xref rid="B146-microorganisms-08-00085" ref-type="bibr">146</xref>,<xref rid="B147-microorganisms-08-00085" ref-type="bibr">147</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Picornaviridae</italic></td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Enteroviruses</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B160-microorganisms-08-00085" ref-type="bibr">160</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro/in vivo (mouse)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B161-microorganisms-08-00085" ref-type="bibr">161</xref>]</td></tr><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Filoviridae</italic></td><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">EBOV</td><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B142-microorganisms-08-00085" ref-type="bibr">142</xref>,<xref rid="B143-microorganisms-08-00085" ref-type="bibr">143</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B142-microorganisms-08-00085" ref-type="bibr">142</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate, amodiaquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B58-microorganisms-08-00085" ref-type="bibr">58</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B132-microorganisms-08-00085" ref-type="bibr">132</xref>]</td></tr><tr><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Retroviridae</italic></td><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HIV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artemisinin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B23-microorganisms-08-00085" ref-type="bibr">23</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Doxycycline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B23-microorganisms-08-00085" ref-type="bibr">23</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine, toremifene, posaconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B132-microorganisms-08-00085" ref-type="bibr">132</xref>]</td></tr><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Chloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B151-microorganisms-08-00085" ref-type="bibr">151</xref>,<xref rid="B157-microorganisms-08-00085" ref-type="bibr">157</xref>,<xref rid="B158-microorganisms-08-00085" ref-type="bibr">158</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vivo</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B155-microorganisms-08-00085" ref-type="bibr">155</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine, hydroxychloroquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">in vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B152-microorganisms-08-00085" ref-type="bibr">152</xref>,<xref rid="B153-microorganisms-08-00085" ref-type="bibr">153</xref>,<xref rid="B154-microorganisms-08-00085" ref-type="bibr">154</xref>,<xref rid="B156-microorganisms-08-00085" ref-type="bibr">156</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Phenuiviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SFTSV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amodiaquine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B163-microorganisms-08-00085" ref-type="bibr">163</xref>]</td></tr></tbody></table></table-wrap><table-wrap id="microorganisms-08-00085-t004" orientation="portrait" position="float"><object-id pub-id-type="pii">microorganisms-08-00085-t004_Table 4</object-id><label>Table 4</label><caption><p>Clinical studies for the assessment of antimalarial drug activity against viral infection.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Virus Family</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Virus Species</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Drug</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">References</th></tr></thead><tbody><tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Herpesviridae</italic></td><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">HCMV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B12-microorganisms-08-00085" ref-type="bibr">12</xref>,<xref rid="B13-microorganisms-08-00085" ref-type="bibr">13</xref>,<xref rid="B46-microorganisms-08-00085" ref-type="bibr">46</xref>,<xref rid="B47-microorganisms-08-00085" ref-type="bibr">47</xref>,<xref rid="B48-microorganisms-08-00085" ref-type="bibr">48</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate-amodiaquine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B49-microorganisms-08-00085" ref-type="bibr">49</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Arthemeter-lumefantrine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B64-microorganisms-08-00085" ref-type="bibr">64</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HHV6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B52-microorganisms-08-00085" ref-type="bibr">52</xref>]</td></tr><tr><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>Polyomaviridae</italic></td><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">JCPyV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-microorganisms-08-00085" ref-type="bibr">54</xref>,<xref rid="B55-microorganisms-08-00085" ref-type="bibr">55</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B72-microorganisms-08-00085" ref-type="bibr">72</xref>,<xref rid="B73-microorganisms-08-00085" ref-type="bibr">73</xref>,<xref rid="B74-microorganisms-08-00085" ref-type="bibr">74</xref>,<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>,<xref rid="B76-microorganisms-08-00085" ref-type="bibr">76</xref>,<xref rid="B77-microorganisms-08-00085" ref-type="bibr">77</xref>,<xref rid="B78-microorganisms-08-00085" ref-type="bibr">78</xref>,<xref rid="B79-microorganisms-08-00085" ref-type="bibr">79</xref>,<xref rid="B80-microorganisms-08-00085" ref-type="bibr">80</xref>,<xref rid="B81-microorganisms-08-00085" ref-type="bibr">81</xref>,<xref rid="B82-microorganisms-08-00085" ref-type="bibr">82</xref>,<xref rid="B83-microorganisms-08-00085" ref-type="bibr">83</xref>,<xref rid="B84-microorganisms-08-00085" ref-type="bibr">84</xref>,<xref rid="B85-microorganisms-08-00085" ref-type="bibr">85</xref>,<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B88-microorganisms-08-00085" ref-type="bibr">88</xref>,<xref rid="B122-microorganisms-08-00085" ref-type="bibr">122</xref>,<xref rid="B123-microorganisms-08-00085" ref-type="bibr">123</xref>,<xref rid="B124-microorganisms-08-00085" ref-type="bibr">124</xref>,<xref rid="B125-microorganisms-08-00085" ref-type="bibr">125</xref>,<xref rid="B126-microorganisms-08-00085" ref-type="bibr">126</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine and mirtazapine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B86-microorganisms-08-00085" ref-type="bibr">86</xref>,<xref rid="B87-microorganisms-08-00085" ref-type="bibr">87</xref>,<xref rid="B89-microorganisms-08-00085" ref-type="bibr">89</xref>,<xref rid="B90-microorganisms-08-00085" ref-type="bibr">90</xref>,<xref rid="B91-microorganisms-08-00085" ref-type="bibr">91</xref>,<xref rid="B92-microorganisms-08-00085" ref-type="bibr">92</xref>,<xref rid="B93-microorganisms-08-00085" ref-type="bibr">93</xref>,<xref rid="B94-microorganisms-08-00085" ref-type="bibr">94</xref>,<xref rid="B95-microorganisms-08-00085" ref-type="bibr">95</xref>,<xref rid="B96-microorganisms-08-00085" ref-type="bibr">96</xref>,<xref rid="B97-microorganisms-08-00085" ref-type="bibr">97</xref>,<xref rid="B98-microorganisms-08-00085" ref-type="bibr">98</xref>,<xref rid="B99-microorganisms-08-00085" ref-type="bibr">99</xref>,<xref rid="B100-microorganisms-08-00085" ref-type="bibr">100</xref>,<xref rid="B101-microorganisms-08-00085" ref-type="bibr">101</xref>,<xref rid="B102-microorganisms-08-00085" ref-type="bibr">102</xref>,<xref rid="B103-microorganisms-08-00085" ref-type="bibr">103</xref>,<xref rid="B104-microorganisms-08-00085" ref-type="bibr">104</xref>,<xref rid="B105-microorganisms-08-00085" ref-type="bibr">105</xref>,<xref rid="B106-microorganisms-08-00085" ref-type="bibr">106</xref>,<xref rid="B107-microorganisms-08-00085" ref-type="bibr">107</xref>,<xref rid="B108-microorganisms-08-00085" ref-type="bibr">108</xref>,<xref rid="B109-microorganisms-08-00085" ref-type="bibr">109</xref>,<xref rid="B110-microorganisms-08-00085" ref-type="bibr">110</xref>,<xref rid="B111-microorganisms-08-00085" ref-type="bibr">111</xref>,<xref rid="B112-microorganisms-08-00085" ref-type="bibr">112</xref>,<xref rid="B113-microorganisms-08-00085" ref-type="bibr">113</xref>,<xref rid="B114-microorganisms-08-00085" ref-type="bibr">114</xref>,<xref rid="B115-microorganisms-08-00085" ref-type="bibr">115</xref>,<xref rid="B116-microorganisms-08-00085" ref-type="bibr">116</xref>,<xref rid="B117-microorganisms-08-00085" ref-type="bibr">117</xref>,<xref rid="B127-microorganisms-08-00085" ref-type="bibr">127</xref>,<xref rid="B128-microorganisms-08-00085" ref-type="bibr">128</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine, mirtazapine and a third drug</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B118-microorganisms-08-00085" ref-type="bibr">118</xref>,<xref rid="B119-microorganisms-08-00085" ref-type="bibr">119</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine and risperidone</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B75-microorganisms-08-00085" ref-type="bibr">75</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine, risperidone and cytarabine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B120-microorganisms-08-00085" ref-type="bibr">120</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine and cidofovir</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B121-microorganisms-08-00085" ref-type="bibr">121</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mefloquine and PML standard of care</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B129-microorganisms-08-00085" ref-type="bibr">129</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Filoviridae</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">EBOV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Artesunate-amodiaquine</td><td align="center" valign="top" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B58-microorganisms-08-00085" ref-type="bibr">58</xref>,<xref rid="B60-microorganisms-08-00085" ref-type="bibr">60</xref>]</td></tr></tbody></table></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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