biostudies-literature00440Hochuli JENational Center for Advancing Translational SciencesNIAID NIH HHSNational Institutes of HealthNIGMS NIH HHS468-478https://www.ebi.ac.uk/biostudies/studies/S-EPMC9236207biostudies-literatureUnknown5(7)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 <i>K</i> _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.ACS pharmacology & translational scienceAllosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents.PMC9236207U19 AI171292T32 GM008570T32GM008570U19AI171292R01 GM140154R01GM140154Jain SMuratov ENBaljinnyam BChoe JTalley DCMelo-Filho CSessions ZLHochuli JERai GBobrowski TZheng JSimeonov ATropsha AEastman RZakharov AV44falseAllosteric 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 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 <i>K</i> _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.2022-01-01T00:00:00Z2022 Jul2024-11-13T17:46:01.011Z2022-07-08T17:38:39.974ZS-EPMC92362073582174610.1021/acsptsci.2c00049