Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

• DOI: 10.1021/acsptsci.2c00206
• Publication Date: 2022-12-28T15:51:33Z
• Authors: Chamandi S. Dampalla; Harry Nhat Nguyen; Athri D. Rathnayake; Yunjeong Kim; Krishani Dinali P...; Trent K. Madden; Hayden A. Thurman; Alexandra J. Machen; Maithri M. Kaship...; Lijun Liu; Kevin P. Battaile; Scott Lovell; Kyeong-Ok Chang; William C. Groutas
• Keywords: Moiety; Mechanism of Action

The advent of SARS-CoV-2, the causative agent COVID-19, and its worldwide impact on global health, have provided impetus for development effective countermeasures that can be deployed against virus, including vaccines, monoclonal antibodies, direct-acting antivirals (DAAs). Despite these efforts, current paucity DAAs has created an urgent need creation enhanced diversified portfolio broadly acting agents with different mechanisms action effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CLpro), enzyme essential replication, is a validated target discovery therapeutics. In this report, we describe structure-guided utilization cyclopropane moiety in design highly potent inhibitors 3CLpro, SARS-CoV-1 MERS-CoV 3CLpro. High-resolution cocrystal structures were used to identify structural determinants associated binding active site unravel mechanism action. Aldehydes 5c 11c inhibited replication EC50 values 12 11 nM, respectively. Furthermore, corresponding aldehyde bisulfite adducts 5d 11d equipotent 13 safety index (SI) compounds / ranged between 7692 9090. Importantly, aldehydes potently 3CLpro IC50 80 120 70 Likewise, 960 350 nM 790 240 Taken together, studies suggest described herein low cytotoxicity high potency are promising candidates further as broad-spectrum pathogenic coronaviruses.