Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents.
ACS Pharmacol Transl Sci
; 5(7): 468-478, 2022 Jul 08.
Article
em En
| MEDLINE
| ID: mdl-35821746
ABSTRACT
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 â¼4%), suggesting they were allosteric binders. Subsequent application of in silico techniques boosted success rates to â¼14% 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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MEDLINE
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En
Ano de publicação:
2022
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Article