Allosteric Binders of ACE2 Are Promising Anti-SARS-CoV-2 Agents
Joshua E. Hochuli, Sankalp Jain, Cleber C. Melo‐Filho, Zoe L. 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
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 ∼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 Kd 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.