Cargando…

Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents

The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can...

Descripción completa

Detalles Bibliográficos
Autores principales: Hochuli, Joshua E., Jain, Sankalp, Melo-Filho, Cleber, Sessions, Zoe L., Bobrowski, Tesia, Choe, Jun, Zheng, Johnny, Eastman, Richard, Talley, Daniel C., Rai, Ganesha, Simeonov, Anton, Tropsha, Alexander, Muratov, Eugene N., Baljinnyam, Bolormaa, Zakharov, Alexey V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936107/
https://www.ncbi.nlm.nih.gov/pubmed/35313579
http://dx.doi.org/10.1101/2022.03.15.484484
_version_ 1784672154661421056
author Hochuli, Joshua E.
Jain, Sankalp
Melo-Filho, Cleber
Sessions, Zoe L.
Bobrowski, Tesia
Choe, Jun
Zheng, Johnny
Eastman, Richard
Talley, Daniel C.
Rai, Ganesha
Simeonov, Anton
Tropsha, Alexander
Muratov, Eugene N.
Baljinnyam, Bolormaa
Zakharov, Alexey V.
author_facet Hochuli, Joshua E.
Jain, Sankalp
Melo-Filho, Cleber
Sessions, Zoe L.
Bobrowski, Tesia
Choe, Jun
Zheng, Johnny
Eastman, Richard
Talley, Daniel C.
Rai, Ganesha
Simeonov, Anton
Tropsha, Alexander
Muratov, Eugene N.
Baljinnyam, Bolormaa
Zakharov, Alexey V.
author_sort Hochuli, Joshua E.
collection PubMed
description The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection.
format Online
Article
Text
id pubmed-8936107
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Cold Spring Harbor Laboratory
record_format MEDLINE/PubMed
spelling pubmed-89361072022-03-22 Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents Hochuli, Joshua E. Jain, Sankalp Melo-Filho, Cleber Sessions, Zoe L. Bobrowski, Tesia Choe, Jun Zheng, Johnny Eastman, Richard Talley, Daniel C. Rai, Ganesha Simeonov, Anton Tropsha, Alexander Muratov, Eugene N. Baljinnyam, Bolormaa Zakharov, Alexey V. bioRxiv Article The COVID-19 pandemic has had enormous health, economic, and social consequences. Vaccines have been successful in reducing rates of infection and hospitalization, but there is still a need for an acute treatment for the disease. We investigate whether compounds that bind the human ACE2 protein can interrupt SARS-CoV-2 replication without damaging ACE2’s natural enzymatic function. Initial compounds were screened for binding to ACE2 but little interruption of ACE2 enzymatic activity. This set of compounds was extended by application of quantitative structure-activity analysis, which resulted in 512 virtual hits for further confirmatory screening. A subsequent SARS-CoV-2 replication assay revealed that five of these compounds inhibit SARS-CoV-2 replication in human cells. Further effort is required to completely determine the antiviral mechanism of these compounds, but they serve as a strong starting point for both development of acute treatments for COVID-19 and research into the mechanism of infection. Cold Spring Harbor Laboratory 2022-03-16 /pmc/articles/PMC8936107/ /pubmed/35313579 http://dx.doi.org/10.1101/2022.03.15.484484 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
Hochuli, Joshua E.
Jain, Sankalp
Melo-Filho, Cleber
Sessions, Zoe L.
Bobrowski, Tesia
Choe, Jun
Zheng, Johnny
Eastman, Richard
Talley, Daniel C.
Rai, Ganesha
Simeonov, Anton
Tropsha, Alexander
Muratov, Eugene N.
Baljinnyam, Bolormaa
Zakharov, Alexey V.
Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title_full Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title_fullStr Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title_full_unstemmed Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title_short Allosteric binders of ACE2 are promising anti-SARS-CoV-2 agents
title_sort allosteric binders of ace2 are promising anti-sars-cov-2 agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936107/
https://www.ncbi.nlm.nih.gov/pubmed/35313579
http://dx.doi.org/10.1101/2022.03.15.484484
work_keys_str_mv AT hochulijoshuae allostericbindersoface2arepromisingantisarscov2agents
AT jainsankalp allostericbindersoface2arepromisingantisarscov2agents
AT melofilhocleber allostericbindersoface2arepromisingantisarscov2agents
AT sessionszoel allostericbindersoface2arepromisingantisarscov2agents
AT bobrowskitesia allostericbindersoface2arepromisingantisarscov2agents
AT choejun allostericbindersoface2arepromisingantisarscov2agents
AT zhengjohnny allostericbindersoface2arepromisingantisarscov2agents
AT eastmanrichard allostericbindersoface2arepromisingantisarscov2agents
AT talleydanielc allostericbindersoface2arepromisingantisarscov2agents
AT raiganesha allostericbindersoface2arepromisingantisarscov2agents
AT simeonovanton allostericbindersoface2arepromisingantisarscov2agents
AT tropshaalexander allostericbindersoface2arepromisingantisarscov2agents
AT muratoveugenen allostericbindersoface2arepromisingantisarscov2agents
AT baljinnyambolormaa allostericbindersoface2arepromisingantisarscov2agents
AT zakharovalexeyv allostericbindersoface2arepromisingantisarscov2agents