Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease.
Dampalla CS, Rathnayake AD, Galasiti Kankanamalage AC, Kim Y, Perera KD, Nguyen HN, Miller MJ, Madden TK, Picard HR, Thurman HA, Kashipathy MM, Liu L, Battaile KP, Lovell S, Chang KO, Groutas WC.
The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CL<sup>pro</sup>) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CL<sup>pro</sup> that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CL<sup>pro</sup> and MERS-CoV 3CL<sup>pro</sup> that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.