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Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents

[Image: see text] 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 acute treatment of the disease. We investigate whether compounds that bind the human ang...

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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: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236207/
https://www.ncbi.nlm.nih.gov/pubmed/35821746
http://dx.doi.org/10.1021/acsptsci.2c00049
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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 [Image: see text] 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 acute treatment of the disease. We investigate whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can decrease SARS-CoV-2 replication without impacting ACE2’s natural enzymatic function. Initial screening of a diversity library resulted in hit compounds active in an ACE2-binding assay, which showed little inhibition of ACE2 enzymatic activity (116 actives, success rate ∼4%), suggesting they were allosteric binders. Subsequent application of in silico techniques boosted success rates to ∼14% and resulted in 73 novel confirmed ACE2 binders with K(d) values as low as 6 nM. A subsequent SARS-CoV-2 assay revealed that five of these compounds inhibit the viral life cycle in human cells. Further effort is required to completely elucidate the antiviral mechanism of these ACE2-binders, but they present a valuable starting point for both the development of acute treatments for COVID-19 and research into the host-directed therapy.
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spelling pubmed-92362072022-06-27 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. ACS Pharmacol Transl Sci [Image: see text] 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 acute treatment of the disease. We investigate whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can decrease SARS-CoV-2 replication without impacting ACE2’s natural enzymatic function. Initial screening of a diversity library resulted in hit compounds active in an ACE2-binding assay, which showed little inhibition of ACE2 enzymatic activity (116 actives, success rate ∼4%), suggesting they were allosteric binders. Subsequent application of in silico techniques boosted success rates to ∼14% and resulted in 73 novel confirmed ACE2 binders with K(d) values as low as 6 nM. A subsequent SARS-CoV-2 assay revealed that five of these compounds inhibit the viral life cycle in human cells. Further effort is required to completely elucidate the antiviral mechanism of these ACE2-binders, but they present a valuable starting point for both the development of acute treatments for COVID-19 and research into the host-directed therapy. American Chemical Society 2022-06-22 /pmc/articles/PMC9236207/ /pubmed/35821746 http://dx.doi.org/10.1021/acsptsci.2c00049 Text en © 2022 American Chemical Society https://pubs.acs.org/page/vi/chemistry_coronavirus_researchThis article is made available via the ACS COVID-19 subset (https://pubs.acs.org/page/vi/chemistry_coronavirus_research) for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle 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
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9236207/
https://www.ncbi.nlm.nih.gov/pubmed/35821746
http://dx.doi.org/10.1021/acsptsci.2c00049
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