Naphthalen-1-ylethanamine–containing small molecule inhibitors of the papain-like protease of SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has not yet been eradicated. SARS-CoV-2 has two types of proteases, a main protease (M pro ) and a papain-like protease (PL pro ), which together process two translated non-structural polyproteins, pp1a and pp1ab, to produce functional viral proteins. In this study, effective inhibitors against PL pro of SARS-CoV-2 were designed and synthesized using GRL-0048 as a lead. A docking simulation of GRL-0048 and SARS-CoV-2 PL pro showed that GRL-0048 noncovalently interacts with PL pro , and there is a newly identified binding pocket in PL pro . Structure-activity relationship studies were next performed on GRL-0048, resulting in the development of several inhibitors, specifically compounds 1 , 2b , and 3h , that have more potent inhibitory activity than GRL-0048. • A papain-like protease (PL pro ) inhibitor GRL-0048 interacts with PL pro . • There is a newly identified binding pocket in PL pro of SARS-CoV-2. • Compounds 1 , 2b , and 3h have more potent inhibitory activity than GRL-0048. • These compounds show hydrogen bond and hydrophobic interactions with PL pro . • Compounds 1 or 3h has no significant cytotoxicity.