Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Abstract

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M^pro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (<b>11a</b> and <b>11b</b>) targeting M^pro Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M^pro in complex with <b>11a</b> or <b>11b</b>, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of <b>11a</b> and <b>11b</b> are covalently bound to cysteine 145 of M^pro Both compounds showed good pharmacokinetic properties in vivo, and <b>11a</b> also exhibited low toxicity, which suggests that these compounds are promising drug candidates.