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

  • Sang Hoon Han
    Sang Hoon Han
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Christopher M. Goins
    Christopher M. Goins
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Tarun Arya
    Tarun Arya
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    More by Tarun Arya
  • Woo-Jin Shin
    Woo-Jin Shin
    Cleveland Clinic Florida Research & Innovation Center, Port St. Lucie, Florida 34987, United States
    More by Woo-Jin Shin
  • Joshua Maw
    Joshua Maw
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    More by Joshua Maw
  • Alice Hooper
    Alice Hooper
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    More by Alice Hooper
  • Dhiraj P. Sonawane
    Dhiraj P. Sonawane
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Matthew R. Porter
    Matthew R. Porter
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Breyanne E. Bannister
    Breyanne E. Bannister
    Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States
  • Rachel D. Crouch
    Rachel D. Crouch
    Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States
  • A. Abigail Lindsey
    A. Abigail Lindsey
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Gabriella Lakatos
    Gabriella Lakatos
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Steven R. Martinez
    Steven R. Martinez
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Joseph Alvarado
    Joseph Alvarado
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Wendell S. Akers
    Wendell S. Akers
    Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States
  • Nancy S. Wang
    Nancy S. Wang
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • Jae U. Jung
    Jae U. Jung
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    Center for Global and Emerging Pathogens Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    More by Jae U. Jung
  • Jonathan D. Macdonald
    Jonathan D. Macdonald
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
  • , and 
  • Shaun R. Stauffer*
    Shaun R. Stauffer
    Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States
    *Email: [email protected]
Cite this: J. Med. Chem. 2022, 65, 4, 2880–2904
Publication Date (Web):August 4, 2021
https://doi.org/10.1021/acs.jmedchem.1c00598
Copyright © 2021 American Chemical Society

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    Supporting Info (2)»

    Abstract

    Abstract Image

    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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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00598.

    • Supplemental figures, SARS-CoV-1 3CLpro X-ray structures, Tier 1 DMPK summary, human S9-generated metabolites and MS fragmentation, X-ray data collection and refinement statistics, ligand electron density maps, UV-based HPLC chromatograms of final compounds, and CPE SARS-CoV-2-infected Vero E6 cell concentration–response curve for 41 (PDF)

    • Molecular formula strings (CSV)

    Accession Codes

    SARS-CoV-2 complexes: 1, PDB entry 7LME; 19, PDB entry 7LMD; 21, PDB entry 7LMF. SARS-CoV-1 complexes: 8, PDB entry 7LMH; 19, PDB entry 7LMI; 21, PDB entry 7LMG; 35, PDB entry 7LMJ.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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