1. Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CL pro ).
- Author
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Han SH, Goins CM, Arya T, Shin WJ, Maw J, Hooper A, Sonawane DP, Porter MR, Bannister BE, Crouch RD, Lindsey AA, Lakatos G, Martinez SR, Alvarado J, Akers WS, Wang NS, Jung JU, Macdonald JD, and Stauffer SR
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, COVID-19 metabolism, Chlorocebus aethiops, Coronavirus 3C Proteases isolation & purification, Coronavirus 3C Proteases metabolism, Crystallography, X-Ray, Cysteine Proteinase Inhibitors chemical synthesis, Cysteine Proteinase Inhibitors chemistry, Dose-Response Relationship, Drug, Glutamine chemistry, Glutamine pharmacology, Humans, Ketones chemistry, Ketones pharmacology, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Peptidomimetics chemistry, SARS-CoV-2 enzymology, Vero Cells, Virus Replication drug effects, COVID-19 Drug Treatment, Antiviral Agents pharmacology, Coronavirus 3C Proteases antagonists & inhibitors, Cysteine Proteinase Inhibitors pharmacology, Peptidomimetics pharmacology, SARS-CoV-2 drug effects
- Abstract
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 SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.- Published
- 2022
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