Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined....

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Autores:
Tipo de recurso:
Article of journal
Fecha de publicación:
2020
Institución:
Universidad de Bogotá Jorge Tadeo Lozano
Repositorio:
Expeditio: repositorio UTadeo
Idioma:
eng
OAI Identifier:
oai:expeditiorepositorio.utadeo.edu.co:20.500.12010/12157
Acceso en línea:
https://www.nature.com/articles/s41422-020-0305-x
http://hdl.handle.net/20.500.12010/12157
https://doi.org/10.1038/s41422-020-0305-x
Palabra clave:
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection
viral infection
Síndrome respiratorio agudo grave
COVID-19
SARS-CoV-2
Coronavirus
Rights
License
Acceso restringido
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oai_identifier_str oai:expeditiorepositorio.utadeo.edu.co:20.500.12010/12157
network_acronym_str UTADEO2
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dc.title.spa.fl_str_mv Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
title Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
spellingShingle Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection
viral infection
Síndrome respiratorio agudo grave
COVID-19
SARS-CoV-2
Coronavirus
title_short Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
title_full Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
title_fullStr Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
title_full_unstemmed Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
title_sort Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion
dc.subject.spa.fl_str_mv Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection
viral infection
topic Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection
viral infection
Síndrome respiratorio agudo grave
COVID-19
SARS-CoV-2
Coronavirus
dc.subject.lemb.spa.fl_str_mv Síndrome respiratorio agudo grave
COVID-19
SARS-CoV-2
Coronavirus
description The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
publishDate 2020
dc.date.accessioned.none.fl_str_mv 2020-08-24T18:07:44Z
dc.date.available.none.fl_str_mv 2020-08-24T18:07:44Z
dc.date.created.none.fl_str_mv 2020-03-30
dc.type.local.spa.fl_str_mv Artículo
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_6501
format http://purl.org/coar/resource_type/c_6501
dc.identifier.other.spa.fl_str_mv https://www.nature.com/articles/s41422-020-0305-x
dc.identifier.uri.none.fl_str_mv http://hdl.handle.net/20.500.12010/12157
dc.identifier.doi.spa.fl_str_mv https://doi.org/10.1038/s41422-020-0305-x
url https://www.nature.com/articles/s41422-020-0305-x
http://hdl.handle.net/20.500.12010/12157
https://doi.org/10.1038/s41422-020-0305-x
dc.language.iso.spa.fl_str_mv eng
language eng
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_16ec
dc.rights.local.spa.fl_str_mv Acceso restringido
rights_invalid_str_mv Acceso restringido
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dc.format.extent.spa.fl_str_mv 13 páginas.
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Cell Research
dc.source.spa.fl_str_mv reponame:Expeditio Repositorio Institucional UJTL
instname:Universidad de Bogotá Jorge Tadeo Lozano
instname_str Universidad de Bogotá Jorge Tadeo Lozano
institution Universidad de Bogotá Jorge Tadeo Lozano
reponame_str Expeditio Repositorio Institucional UJTL
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spelling 2020-08-24T18:07:44Z2020-08-24T18:07:44Z2020-03-30https://www.nature.com/articles/s41422-020-0305-xhttp://hdl.handle.net/20.500.12010/12157https://doi.org/10.1038/s41422-020-0305-x13 páginas.application/pdfengCell Researchreponame:Expeditio Repositorio Institucional UJTLinstname:Universidad de Bogotá Jorge Tadeo LozanoInhibition of SARS-CoV-2 (previously 2019-nCoV) infectionviral infectionSíndrome respiratorio agudo graveCOVID-19SARS-CoV-2CoronavirusInhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusionArtículohttp://purl.org/coar/resource_type/c_6501Acceso restringidohttp://purl.org/coar/access_right/c_16ecThe recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell–cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.Xia, ShuaiLiu, MeiqinWang, ChaoXu, WeiLan, QiaoshuaiFeng, SiliangQi, FeifeiBao, LinlinDu, LanyingLiu, ShuwenQin, ChuanSun, FeiShi, ZhengliZhu, YunJiang, ShiboLu LuORIGINALInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pdfInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pdfArticulo de Revistaapplication/pdf5637323https://expeditiorepositorio.utadeo.edu.co/bitstream/20.500.12010/12157/3/Inhibition%20of%20SARS-CoV-2%20%28previously%202019-nCoV%29%20infection.pdfdabf0e33007760a2ab85682f033ac045MD53embargoed access|||2420-08-24LICENSElicense.txtlicense.txttext/plain; charset=utf-82938https://expeditiorepositorio.utadeo.edu.co/bitstream/20.500.12010/12157/2/license.txtabceeb1c943c50d3343516f9dbfc110fMD52open accessTHUMBNAILInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pngInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pngimage/png128512https://expeditiorepositorio.utadeo.edu.co/bitstream/20.500.12010/12157/4/Inhibition%20of%20SARS-CoV-2%20%28previously%202019-nCoV%29%20infection.png2dd24c624842afcdab9a2cbf1b4b1616MD54open accessInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pdf.jpgInhibition of SARS-CoV-2 (previously 2019-nCoV) infection.pdf.jpgIM Thumbnailimage/jpeg23859https://expeditiorepositorio.utadeo.edu.co/bitstream/20.500.12010/12157/5/Inhibition%20of%20SARS-CoV-2%20%28previously%202019-nCoV%29%20infection.pdf.jpgbd9281c136f82361b0488cebcf9e32fdMD55open access20.500.12010/12157oai:expeditiorepositorio.utadeo.edu.co:20.500.12010/121572020-08-24 13:11:55.81embargoed access|||2420-08-24Repositorio Institucional - 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