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A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced 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 identifie...

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Autores principales: 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., Liu, Jie, Myerburg, Michael M., McDyer, John F., Liu, Yuan, Finkel, Toren, Chen, Bill B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430593/
https://www.ncbi.nlm.nih.gov/pubmed/32818215
http://dx.doi.org/10.21203/rs.3.rs-48659/v1
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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.
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.
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 identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent 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, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. 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 COVID-19 infection.
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spelling pubmed-74305932020-08-18 A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced 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. Liu, Jie Myerburg, Michael M. McDyer, John F. Liu, Yuan Finkel, Toren Chen, Bill B. Res Sq 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 identified small molecules that can reduce surface expression of TMPRSS2 using a 2,700 FDA-approved or current clinical trial compounds. Among these, homoharringtonine and halofuginone appear the most potent 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, demonstrated marked resistance to SARS-CoV-2 pseudoviral infection. 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 COVID-19 infection. American Journal Experts 2020-08-14 /pmc/articles/PMC7430593/ /pubmed/32818215 http://dx.doi.org/10.21203/rs.3.rs-48659/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
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.
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 and clinically advanced compounds that can limit SARS-CoV-2 entry
title A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry
title_full A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry
title_fullStr A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry
title_full_unstemmed A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry
title_short A high throughput screen for TMPRSS2 expression identifies FDA-approved and clinically advanced compounds that can limit SARS-CoV-2 entry
title_sort high throughput screen for tmprss2 expression identifies fda-approved and clinically advanced compounds that can limit sars-cov-2 entry
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430593/
https://www.ncbi.nlm.nih.gov/pubmed/32818215
http://dx.doi.org/10.21203/rs.3.rs-48659/v1
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