Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain

ABSTRACT The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The developm...

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Autores principales:	Victor K. Outlaw, Francesca T. Bovier, Megan C. Mears, Maria N. Cajimat, Yun Zhu, Michelle J. Lin, Amin Addetia, Nicole A. P. Lieberman, Vikas Peddu, Xuping Xie, Pei-Yong Shi, Alexander L. Greninger, Samuel H. Gellman, Dennis A. Bente, Anne Moscona, Matteo Porotto
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	SARS-CoV-2 spike protein fusion inhibitor lipopeptide Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/67347a10ef8144ada066a6a8fb7f2582
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spelling	oai:doaj.org-article:67347a10ef8144ada066a6a8fb7f25822021-11-15T16:19:09ZInhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain10.1128/mBio.01935-202150-7511https://doaj.org/article/67347a10ef8144ada066a6a8fb7f25822020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01935-20https://doaj.org/toc/2150-7511ABSTRACT The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.Victor K. OutlawFrancesca T. BovierMegan C. MearsMaria N. CajimatYun ZhuMichelle J. LinAmin AddetiaNicole A. P. LiebermanVikas PedduXuping XiePei-Yong ShiAlexander L. GreningerSamuel H. GellmanDennis A. BenteAnne MosconaMatteo PorottoAmerican Society for MicrobiologyarticleSARS-CoV-2spike proteinfusion inhibitorlipopeptideMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	SARS-CoV-2 spike protein fusion inhibitor lipopeptide Microbiology QR1-502
spellingShingle	SARS-CoV-2 spike protein fusion inhibitor lipopeptide Microbiology QR1-502 Victor K. Outlaw Francesca T. Bovier Megan C. Mears Maria N. Cajimat Yun Zhu Michelle J. Lin Amin Addetia Nicole A. P. Lieberman Vikas Peddu Xuping Xie Pei-Yong Shi Alexander L. Greninger Samuel H. Gellman Dennis A. Bente Anne Moscona Matteo Porotto Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
description	ABSTRACT The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.
format	article
author	Victor K. Outlaw Francesca T. Bovier Megan C. Mears Maria N. Cajimat Yun Zhu Michelle J. Lin Amin Addetia Nicole A. P. Lieberman Vikas Peddu Xuping Xie Pei-Yong Shi Alexander L. Greninger Samuel H. Gellman Dennis A. Bente Anne Moscona Matteo Porotto
author_facet	Victor K. Outlaw Francesca T. Bovier Megan C. Mears Maria N. Cajimat Yun Zhu Michelle J. Lin Amin Addetia Nicole A. P. Lieberman Vikas Peddu Xuping Xie Pei-Yong Shi Alexander L. Greninger Samuel H. Gellman Dennis A. Bente Anne Moscona Matteo Porotto
author_sort	Victor K. Outlaw
title	Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
title_short	Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
title_full	Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
title_fullStr	Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
title_full_unstemmed	Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain
title_sort	inhibition of coronavirus entry <italic toggle="yes">in vitro</italic> and <italic toggle="yes">ex vivo</italic> by a lipid-conjugated peptide derived from the sars-cov-2 spike glycoprotein hrc domain
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/67347a10ef8144ada066a6a8fb7f2582
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Inhibition of Coronavirus Entry <italic toggle="yes">In Vitro</italic> and <italic toggle="yes">Ex Vivo</italic> by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain

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