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

Autor: Hochuli JE; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.; Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Jain S; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Melo-Filho C; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Sessions ZL; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Bobrowski T; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Choe J; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Zheng J; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Eastman R; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Talley DC; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Rai G; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Simeonov A; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Tropsha A; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Muratov EN; Molecular Modeling Laboratory, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States., Baljinnyam B; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States., Zakharov AV; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20850, United States.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2022 Jun 22; Vol. 5 (7), pp. 468-478. Date of Electronic Publication: 2022 Jun 22 (Print Publication: 2022).
DOI: 10.1021/acsptsci.2c00049
Abstrakt: 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.
Competing Interests: The authors declare the following competing financial interest(s): A.T. and E.N.M. are co-founders of Predictive, LLC, which develops computational methodologies and software for toxicity prediction.
(© 2022 American Chemical Society.)
Databáze: MEDLINE
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