A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike.
Identifieur interne : 000566 ( PubMed/Corpus ); précédent : 000565; suivant : 000567A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike.
Auteurs : Shuai Xia ; Lei Yan ; Wei Xu ; Anurodh Shankar Agrawal ; Abdullah Algaissi ; Chien-Te K. Tseng ; Qian Wang ; Lanying Du ; Wenjie Tan ; Ian A. Wilson ; Shibo Jiang ; Bei Yang ; Lu LuSource :
- Science advances [ 2375-2548 ] ; 2019.
Abstract
Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.
DOI: 10.1126/sciadv.aav4580
PubMed: 30989115
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Tseng</name><affiliation><nlm:affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation><nlm:affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:affiliation></affiliation></author><author><name sortKey="Du, Lanying" sort="Du, Lanying" uniqKey="Du L" first="Lanying" last="Du">Lanying Du</name><affiliation><nlm:affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</nlm:affiliation></affiliation></author><author><name sortKey="Tan, Wenjie" sort="Tan, Wenjie" uniqKey="Tan W" first="Wenjie" last="Tan">Wenjie Tan</name><affiliation><nlm:affiliation>MOH Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.</nlm:affiliation></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A" last="Wilson">Ian A. Wilson</name><affiliation><nlm:affiliation>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</nlm:affiliation></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:affiliation></affiliation></author><author><name sortKey="Yang, Bei" sort="Yang, Bei" uniqKey="Yang B" first="Bei" last="Yang">Bei Yang</name><affiliation><nlm:affiliation>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</nlm:affiliation></affiliation></author><author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name><affiliation><nlm:affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Science advances</title><idno type="eISSN">2375-2548</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">30989115</PMID><DateRevised><Year>2020</Year><Month>03</Month><Day>10</Day></DateRevised><Article PubModel="Electronic-eCollection"><Journal><ISSN IssnType="Electronic">2375-2548</ISSN><JournalIssue CitedMedium="Internet"><Volume>5</Volume><Issue>4</Issue><PubDate><Year>2019</Year><Month>04</Month></PubDate></JournalIssue><Title>Science advances</Title><ISOAbbreviation>Sci Adv</ISOAbbreviation></Journal><ArticleTitle>A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike.</ArticleTitle><Pagination><MedlinePgn>eaav4580</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1126/sciadv.aav4580</ELocationID><Abstract><AbstractText>Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs. EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Xia</LastName><ForeName>Shuai</ForeName><Initials>S</Initials><Identifier Source="ORCID">0000-0001-7896-4182</Identifier><AffiliationInfo><Affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yan</LastName><ForeName>Lei</ForeName><Initials>L</Initials><Identifier Source="ORCID">0000-0003-1775-5533</Identifier><AffiliationInfo><Affiliation>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Xu</LastName><ForeName>Wei</ForeName><Initials>W</Initials><Identifier Source="ORCID">0000-0003-3013-7182</Identifier><AffiliationInfo><Affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Agrawal</LastName><ForeName>Anurodh Shankar</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Algaissi</LastName><ForeName>Abdullah</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tseng</LastName><ForeName>Chien-Te K</ForeName><Initials>CK</Initials><AffiliationInfo><Affiliation>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Qian</ForeName><Initials>Q</Initials><AffiliationInfo><Affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Du</LastName><ForeName>Lanying</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Tan</LastName><ForeName>Wenjie</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>MOH Key Laboratory of Medical Virology, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wilson</LastName><ForeName>Ian A</ForeName><Initials>IA</Initials><Identifier Source="ORCID">0000-0002-6469-2419</Identifier><AffiliationInfo><Affiliation>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Integrative Structural and Computational Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC206, La Jolla, CA 92037, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jiang</LastName><ForeName>Shibo</ForeName><Initials>S</Initials><Identifier Source="ORCID">0000-0003-1493-6523</Identifier><AffiliationInfo><Affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yang</LastName><ForeName>Bei</ForeName><Initials>B</Initials><Identifier Source="ORCID">0000-0001-5389-3859</Identifier><AffiliationInfo><Affiliation>Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lu</LastName><ForeName>Lu</ForeName><Initials>L</Initials><Identifier Source="ORCID">0000-0002-2255-0391</Identifier><AffiliationInfo><Affiliation>Shanghai Public Health Clinical Center and School of Basic Medical Sciences, and Key Laboratory of Medical Molecular Virology of MOE/MOH, Fudan University, Shanghai 200032, China.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>UM1 AI100663</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH 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