Open AccessAllosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents
Author(s) -
Joshua Hochuli,
Sankalp Jain,
Cleber C. Melo-Filho,
Zoe Sessions,
Tesia Bobrowski,
Jun Choe,
Johnny Zheng,
Richard T. Eastman,
Daniel C. Talley,
Ganesha Rai,
Anton Simeonov,
Alexander Tropsha,
Eugene Muratov,
Bolormaa Baljinnyam,
Alexey Zakharov
Publication year - 2022
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.2c00049
Subject(s) - allosteric regulation , angiotensin converting enzyme 2 , covid-19 , enzyme , in silico , viral replication , chemistry , drug discovery , virology , pharmacology , computational biology , biology , biochemistry , virus , disease , medicine , gene , infectious disease (medical specialty) , pathology , outbreak
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.