Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents.
ACS Pharmacol Transl Sci
; 5(7): 468-478, 2022 Jul 08.
Article
en 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
ACS Pharmacol Transl Sci
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos