Abstract
<jats:p>The coronavirus main protease (Mpro, 3CLpro) remains an attractive target for the development of antiviral therapeutics due to its essential role in viral replication and high sequence conservation across coronaviruses. The oxamide functionality represents a versatile medicinal chemistry motif capable of acting as both a hydrogen-bond donor and acceptor while imparting conformational constraint to bioactive molecules. Building on an oxamide-based hit compound, we designed, synthesized, and evaluated an expanded series of Nterminal oxamide capped peptidomimetics to optimize antiviral potency and developability. Structure-activity relationship studies explored variations in the oxamide P2-cap as a function of proline and non-proline modifications at the P2 motif. Evaluation against SARS-CoV-2 identified multiple analogs with sub-100 nM antiviral activity while maintaining favorable metabolic stability in microsomes. Among these, mCMV911 emerged as a lead candidate, exhibiting broad-spectrum antiviral activity (e.g., ALI-HBEC SARS-CoV-2 EC90 = 19 nM, HCoV-OC43 EC90 = 186 nM, HCoV-229E EC90 = 59 nM), while maintaining favorable aqueous solubility (0.4-0.7 mg/mL), moderate microsomal stability, and oral bioavailability (FPO = 22% in dogs). Furthermore, we discuss the pharmacokinetic properties of mCMV911, and proof-of-concept efficacy data from a coronavirus mouse model.</jats:p>