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A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry
SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222394/ https://www.ncbi.nlm.nih.gov/pubmed/34162861 http://dx.doi.org/10.1038/s41467-021-24156-y |
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author | Chen, Yanwen Lear, Travis B. Evankovich, John W. Larsen, Mads B. Lin, Bo Alfaras, Irene Kennerdell, Jason R. Salminen, Laura Camarco, Daniel P. Lockwood, Karina C. Tuncer, Ferhan Liu, Jie Myerburg, Michael M. McDyer, John F. Liu, Yuan Finkel, Toren Chen, Bill B. |
author_facet | Chen, Yanwen Lear, Travis B. Evankovich, John W. Larsen, Mads B. Lin, Bo Alfaras, Irene Kennerdell, Jason R. Salminen, Laura Camarco, Daniel P. Lockwood, Karina C. Tuncer, Ferhan Liu, Jie Myerburg, Michael M. McDyer, John F. Liu, Yuan Finkel, Toren Chen, Bill B. |
author_sort | Chen, Yanwen |
collection | PubMed |
description | SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection. |
format | Online Article Text |
id | pubmed-8222394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82223942021-07-09 A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry Chen, Yanwen Lear, Travis B. Evankovich, John W. Larsen, Mads B. Lin, Bo Alfaras, Irene Kennerdell, Jason R. Salminen, Laura Camarco, Daniel P. Lockwood, Karina C. Tuncer, Ferhan Liu, Jie Myerburg, Michael M. McDyer, John F. Liu, Yuan Finkel, Toren Chen, Bill B. Nat Commun Article SARS-CoV-2 (2019-nCoV) is the pathogenic coronavirus responsible for the global pandemic of COVID-19 disease. The Spike (S) protein of SARS-CoV-2 attaches to host lung epithelial cells through the cell surface receptor ACE2, a process dependent on host proteases including TMPRSS2. Here, we identify small molecules that reduce surface expression of TMPRSS2 using a library of 2,560 FDA-approved or current clinical trial compounds. We identify homoharringtonine and halofuginone as the most attractive agents, reducing endogenous TMPRSS2 expression at sub-micromolar concentrations. These effects appear to be mediated by a drug-induced alteration in TMPRSS2 protein stability. We further demonstrate that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1 (DCAF1). Finally, cells exposed to homoharringtonine and halofuginone, at concentrations of drug known to be achievable in human plasma, demonstrate marked resistance to SARS-CoV-2 infection in both live and pseudoviral in vitro models. Given the safety and pharmacokinetic data already available for the compounds identified in our screen, these results should help expedite the rational design of human clinical trials designed to combat active COVID-19 infection. Nature Publishing Group UK 2021-06-23 /pmc/articles/PMC8222394/ /pubmed/34162861 http://dx.doi.org/10.1038/s41467-021-24156-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chen, Yanwen Lear, Travis B. Evankovich, John W. Larsen, Mads B. Lin, Bo Alfaras, Irene Kennerdell, Jason R. Salminen, Laura Camarco, Daniel P. Lockwood, Karina C. Tuncer, Ferhan Liu, Jie Myerburg, Michael M. McDyer, John F. Liu, Yuan Finkel, Toren Chen, Bill B. A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title | A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title_full | A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title_fullStr | A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title_full_unstemmed | A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title_short | A high-throughput screen for TMPRSS2 expression identifies FDA-approved compounds that can limit SARS-CoV-2 entry |
title_sort | high-throughput screen for tmprss2 expression identifies fda-approved compounds that can limit sars-cov-2 entry |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222394/ https://www.ncbi.nlm.nih.gov/pubmed/34162861 http://dx.doi.org/10.1038/s41467-021-24156-y |
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