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Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.
Ma, Chunlong; Xia, Zilei; Sacco, Michael Dominic; Hu, Yanmei; Townsend, Julia Alma; Meng, Xiangzhi; Choza, Juliana; Tan, Haozhou; Jang, Janice; Gongora, Maura V; Zhang, Xiujun; Zhang, Fushun; Xiang, Yan; Marty, Michael Thomas; Chen, Yu; Wang, Jun.
  • Ma C; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Xia Z; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Sacco MD; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • Hu Y; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Townsend JA; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
  • Meng X; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Choza J; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Tan H; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Jang J; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • Gongora MV; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • Zhang X; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • Zhang F; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Xiang Y; Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
  • Marty MT; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States.
  • Chen Y; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • Wang J; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
J Am Chem Soc ; 143(49): 20697-20709, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1550253
ABSTRACT
The main protease (Mpro) is a validated antiviral drug target of SARS-CoV-2. A number of Mpro inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 Mpro inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates Jun9-62-2R (dichloroacetamide) and Jun9-88-6R (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to GC-376, these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent Mpro inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 Mpro with Jun9-62-2R and Jun9-57-3R reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / Acetamides Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Am Chem Soc Year: 2021 Document Type: Article Affiliation country: Jacs.1c08060

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / Acetamides Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Am Chem Soc Year: 2021 Document Type: Article Affiliation country: Jacs.1c08060