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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).
Han, Sang Hoon; Goins, Christopher M; Arya, Tarun; Shin, Woo-Jin; Maw, Joshua; Hooper, Alice; Sonawane, Dhiraj P; Porter, Matthew R; Bannister, Breyanne E; Crouch, Rachel D; Lindsey, A Abigail; Lakatos, Gabriella; Martinez, Steven R; Alvarado, Joseph; Akers, Wendell S; Wang, Nancy S; Jung, Jae U; Macdonald, Jonathan D; Stauffer, Shaun R.
  • Han SH; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Goins CM; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Arya T; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Shin WJ; Cleveland Clinic Florida Research & Innovation Center, Port St. Lucie, Florida 34987, United States.
  • Maw J; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Hooper A; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Sonawane DP; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Porter MR; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Bannister BE; Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States.
  • Crouch RD; Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States.
  • Lindsey AA; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Lakatos G; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Martinez SR; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Alvarado J; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Akers WS; Department of Pharmaceutical Science, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States.
  • Wang NS; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Jung JU; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Macdonald JD; Center for Global and Emerging Pathogens Research, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
  • Stauffer SR; Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1705973
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Peptidomimetics / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.1c00598

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Peptidomimetics / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2022 Document Type: Article Affiliation country: Acs.jmedchem.1c00598