2. Academic Validation
  3. Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro)

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro)

  • J Med Chem. 2022 Feb 24;65(4):2880-2904. doi: 10.1021/acs.jmedchem.1c00598.
Sang Hoon Han 1,  Christopher M Goins 1,  Tarun Arya 1,  Woo-Jin Shin 2,  Joshua Maw 1,  Alice Hooper 1,  Dhiraj P Sonawane 1,  Matthew R Porter 1,  Breyanne E Bannister 3,  Rachel D Crouch 3,  A Abigail Lindsey 1,  Gabriella Lakatos 1,  Steven R Martinez 1,  Joseph Alvarado 1,  Wendell S Akers 3,  Nancy S Wang 1,  Jae U Jung 4 5,  Jonathan D Macdonald 1,  Shaun R Stauffer 1
Affiliations

Affiliations

  • 1 Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • 2 Cleveland Clinic Florida Research & Innovation Center, Port St. Lucie, Florida 34987, United States.
  • 3 Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States.
  • 4 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • 5 Center for Global and Emerging Pathogens Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
PMID: 34347470 DOI: 10.1021/acs.jmedchem.1c00598
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 (3CLpro). 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.

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