Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

TLDR

The COVID‑19 pandemic caused by SARS‑CoV‑2 has resulted in millions of deaths and underscores the urgent need for effective oral antiviral drugs. The study reports the discovery of S‑217622, the first oral noncovalent, nonpeptidic SARS‑CoV‑2 3CL protease inhibitor clinical candidate. S‑217622 was identified through virtual screening and an in‑house compound library, then optimized via structure‑based drug design. S‑217622 shows potent in‑vitro antiviral activity against circulating SARS‑CoV‑2 variants, favorable once‑daily oral pharmacokinetics, and dose‑dependent suppression of pulmonary viral replication in mice.

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral noncovalent, nonpeptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel noncovalent inhibitor could be a potential oral agent for treating COVID-19.