Structure-based optimization of ML300 derived, non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 3CL protease (SARS-CoV-2 3CLpro)

Starting from the MLPCN probe compound ML300 a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CL pro ). X-ray structures of SARS-CoV-1 and CoV-2 3CL pro enzymes in complex with multiple ML300 based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry towards probe compound 41 (CCF0058981). The inhibitors disclosed utilize a non-covalent mode of action and complex in a non-canonical binding mode not observed by peptidic 3CL pro inhibitors. In vitro DMPK profiling highlight key areas where further optimization in the series is required to obtain useful in vivo probes. Anti-viral activity was established using a SARS-CoV-2 infected Vero E6 cell viability assay, and in a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications towards antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.