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Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor

Identifieur interne : 001565 ( Main/Exploration ); précédent : 001564; suivant : 001566

Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor

Auteurs : Lu Lu [République populaire de Chine] ; Qi Liu [République populaire de Chine] ; Yun Zhu [République populaire de Chine] ; Kwok-Hung Chan [Hong Kong] ; Lili Qin [République populaire de Chine] ; Yuan Li [République populaire de Chine] ; Qian Wang [République populaire de Chine] ; Jasper Fuk-Woo Chan [Hong Kong] ; Lanying Du [États-Unis] ; Fei Yu [États-Unis] ; Cuiqing Ma [États-Unis] ; Sheng Ye [République populaire de Chine] ; Kwok-Yung Yuen [Hong Kong] ; Rongguang Zhang [République populaire de Chine] ; Shibo Jiang [République populaire de Chine, États-Unis]

Source :

RBID : PMC:7091805

Descripteurs français

English descriptors

Abstract

A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998–1039 in HR1 and 1251–1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell–cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.

Supplementary information

The online version of this article (doi:10.1038/ncomms4067) contains supplementary material, which is available to authorized users.


Url:
DOI: 10.1038/ncomms4067
PubMed: 24473083
PubMed Central: 7091805


Affiliations:


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<name sortKey="Ma, Cuiqing" sort="Ma, Cuiqing" uniqKey="Ma C" first="Cuiqing" last="Ma">Cuiqing Ma</name>
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<institution>Lindsley F. Kimball Research Institute, New York Blood Center,</institution>
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New York, 10065 New York USA</nlm:aff>
<country>États-Unis</country>
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<settlement type="city">New York</settlement>
<region type="state">État de New York</region>
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<wicri:regionArea>New York</wicri:regionArea>
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</author>
<author>
<name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name>
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<nlm:aff id="Aff2">
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<institution-id institution-id-type="GRID">grid.418856.6</institution-id>
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<institution>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,</institution>
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Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
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<nlm:aff id="Aff3">
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<institution-id institution-id-type="GRID">grid.194645.b</institution-id>
<institution-id institution-id-type="ISNI">0000000121742757</institution-id>
<institution>Department of Microbiology,</institution>
<institution>State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong,</institution>
</institution-wrap>
Pokfulam, Hong Kong</nlm:aff>
<country xml:lang="fr">Hong Kong</country>
<wicri:regionArea>Pokfulam</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zhang, Rongguang" sort="Zhang, Rongguang" uniqKey="Zhang R" first="Rongguang" last="Zhang">Rongguang Zhang</name>
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<nlm:aff id="Aff2">
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<institution-id institution-id-type="GRID">grid.418856.6</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 1792 5640</institution-id>
<institution>National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,</institution>
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Beijing, 100101 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Beijing</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<affiliation wicri:level="1">
<nlm:aff id="Aff1">
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<institution-id institution-id-type="GRID">grid.8547.e</institution-id>
<institution-id institution-id-type="ISNI">0000 0001 0125 2443</institution-id>
<institution>Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University,</institution>
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Shanghai, 200032 China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Shanghai</wicri:regionArea>
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<affiliation wicri:level="1">
<nlm:aff id="Aff4">
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<institution-id institution-id-type="GRID">grid.250415.7</institution-id>
<institution-id institution-id-type="ISNI">0000 0004 0442 2075</institution-id>
<institution>Lindsley F. Kimball Research Institute, New York Blood Center,</institution>
</institution-wrap>
New York, 10065 New York USA</nlm:aff>
<country>États-Unis</country>
<placeName>
<settlement type="city">New York</settlement>
<region type="state">État de New York</region>
</placeName>
<wicri:regionArea>New York</wicri:regionArea>
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</author>
</analytic>
<series>
<title level="j">Nature Communications</title>
<idno type="eISSN">2041-1723</idno>
<imprint>
<date when="2014">2014</date>
</imprint>
</series>
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<textClass>
<keywords scheme="KwdEn" xml:lang="en">
<term>Amino Acid Sequence</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Middle East Respiratory Syndrome Coronavirus (metabolism)</term>
<term>Molecular Sequence Data</term>
<term>Peptides (chemistry)</term>
<term>Peptides (metabolism)</term>
<term>Spike Glycoprotein, Coronavirus (chemistry)</term>
<term>Spike Glycoprotein, Coronavirus (metabolism)</term>
<term>Viral Fusion Proteins (antagonists & inhibitors)</term>
<term>Viral Fusion Proteins (metabolism)</term>
<term>Viral Proteins (chemistry)</term>
<term>Viral Proteins (metabolism)</term>
<term>Virus Internalization</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Coronavirus du syndrome respiratoire du Moyen-Orient (métabolisme)</term>
<term>Cristallographie aux rayons X</term>
<term>Données de séquences moléculaires</term>
<term>Glycoprotéine de spicule des coronavirus ()</term>
<term>Glycoprotéine de spicule des coronavirus (métabolisme)</term>
<term>Humains</term>
<term>Peptides ()</term>
<term>Peptides (métabolisme)</term>
<term>Protéines de fusion virale (antagonistes et inhibiteurs)</term>
<term>Protéines de fusion virale (métabolisme)</term>
<term>Protéines virales ()</term>
<term>Protéines virales (métabolisme)</term>
<term>Pénétration virale</term>
<term>Réplication virale</term>
<term>Séquence d'acides aminés</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en">
<term>Viral Fusion Proteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en">
<term>Peptides</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr">
<term>Protéines de fusion virale</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en">
<term>Middle East Respiratory Syndrome Coronavirus</term>
<term>Peptides</term>
<term>Spike Glycoprotein, Coronavirus</term>
<term>Viral Fusion Proteins</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Coronavirus du syndrome respiratoire du Moyen-Orient</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Peptides</term>
<term>Protéines de fusion virale</term>
<term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Amino Acid Sequence</term>
<term>Crystallography, X-Ray</term>
<term>Humans</term>
<term>Molecular Sequence Data</term>
<term>Virus Internalization</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr">
<term>Cristallographie aux rayons X</term>
<term>Données de séquences moléculaires</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Humains</term>
<term>Peptides</term>
<term>Protéines virales</term>
<term>Pénétration virale</term>
<term>Réplication virale</term>
<term>Séquence d'acides aminés</term>
</keywords>
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<front>
<div type="abstract" xml:lang="en">
<p id="Par1">A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998–1039 in HR1 and 1251–1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell–cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.</p>
<sec>
<title>Supplementary information</title>
<p>The online version of this article (doi:10.1038/ncomms4067) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<name sortKey="Emsley, P" uniqKey="Emsley P">P Emsley</name>
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<name sortKey="Cowtan, K" uniqKey="Cowtan K">K Cowtan</name>
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<author>
<name sortKey="Chau, Kh" uniqKey="Chau K">KH Chau</name>
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<author>
<name sortKey="Xu, Z" uniqKey="Xu Z">Z Xu</name>
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<author>
<name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name>
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</analytic>
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<name sortKey="Chou, Tc" uniqKey="Chou T">TC Chou</name>
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<analytic>
<author>
<name sortKey="He, Y" uniqKey="He Y">Y He</name>
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<name sortKey="Lu, H" uniqKey="Lu H">H Lu</name>
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<name sortKey="Siddiqui, P" uniqKey="Siddiqui P">P Siddiqui</name>
</author>
<author>
<name sortKey="Zhou, Y" uniqKey="Zhou Y">Y Zhou</name>
</author>
<author>
<name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name>
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<analytic>
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<name sortKey="Zhao, G" uniqKey="Zhao G">G Zhao</name>
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<analytic>
<author>
<name sortKey="Jiang, S" uniqKey="Jiang S">S Jiang</name>
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<list>
<country>
<li>Hong Kong</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
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<li>État de New York</li>
</region>
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<li>New York</li>
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<name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name>
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<name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<name sortKey="Li, Yuan" sort="Li, Yuan" uniqKey="Li Y" first="Yuan" last="Li">Yuan Li</name>
<name sortKey="Liu, Qi" sort="Liu, Qi" uniqKey="Liu Q" first="Qi" last="Liu">Qi Liu</name>
<name sortKey="Qin, Lili" sort="Qin, Lili" uniqKey="Qin L" first="Lili" last="Qin">Lili Qin</name>
<name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name>
<name sortKey="Ye, Sheng" sort="Ye, Sheng" uniqKey="Ye S" first="Sheng" last="Ye">Sheng Ye</name>
<name sortKey="Zhang, Rongguang" sort="Zhang, Rongguang" uniqKey="Zhang R" first="Rongguang" last="Zhang">Rongguang Zhang</name>
<name sortKey="Zhu, Yun" sort="Zhu, Yun" uniqKey="Zhu Y" first="Yun" last="Zhu">Yun Zhu</name>
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<country name="Hong Kong">
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<name sortKey="Chan, Kwok Hung" sort="Chan, Kwok Hung" uniqKey="Chan K" first="Kwok-Hung" last="Chan">Kwok-Hung Chan</name>
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<name sortKey="Chan, Jasper Fuk Woo" sort="Chan, Jasper Fuk Woo" uniqKey="Chan J" first="Jasper Fuk-Woo" last="Chan">Jasper Fuk-Woo Chan</name>
<name sortKey="Yuen, Kwok Yung" sort="Yuen, Kwok Yung" uniqKey="Yuen K" first="Kwok-Yung" last="Yuen">Kwok-Yung Yuen</name>
</country>
<country name="États-Unis">
<region name="État de New York">
<name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name>
</region>
<name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name>
<name sortKey="Ma, Cuiqing" sort="Ma, Cuiqing" uniqKey="Ma C" first="Cuiqing" last="Ma">Cuiqing Ma</name>
<name sortKey="Yu, Fei" sort="Yu, Fei" uniqKey="Yu F" first="Fei" last="Yu">Fei Yu</name>
</country>
</tree>
</affiliations>
</record>

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