ABSTRACT We report here the discovery of several highly potent small molecules that showed low nM potency against SARS-CoV (IC 50 : as low as 13 nM), SARS-CoV-2 (IC 50 : as low as 23 nM), and MERS-CoV (IC 50 : as low as 76 nM) in pseudovirus based assays with excellent selectivity indices (SI: as high as &gt; 5000) demonstrating their pancoronavirus inhibition. Some compounds also show 100% inhibition of CPE (IC 100 ) at 1.25 µM against an authentic SARS-CoV-2 (US_WA-1/2020). Furthermore, the most active inhibitors also potently inhibited variants of concerns (VOCs), such as the UK (B.1.1.7), South Africa (B.1.351), and Delta variant (B.1.617.2), originated in India. We confirmed that one of the potent inhibitors binds to the prefusion spike protein trimer of SARS-CoV-2 by SPR. Besides, we showed that they inhibit virus-mediated cell-cell fusion. The ADME data of one of the most active inhibitors, NBCoV1, show drug-like properties. In vivo PK of NBCoV1 in rats demonstrated excellent half-life (t1/2) of 11.3 h, mean resident time (MRT) of 14.2 h, and oral bioavailability. We expect the lead inhibitors to pave the way for further development to preclinical and clinical candidates.

Discovery of highly potent pancoronavirus fusion inhibitors that also effectively inhibit COVID-19 variants from the UK (Alpha), South Africa (Beta), and India (Delta)