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....
- 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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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 http://purl.org/coar/access_right/c_16ec |
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 |
collection |
Expeditio Repositorio Institucional UJTL |
bitstream.url.fl_str_mv |
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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 - Universidad Jorge Tadeo Lozanoexpeditio@utadeo.edu.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 |