Cannabinoid-Inspired Inhibitors of the SARS-CoV-2 Coronavirus 2'- O -Methyltransferase (2'- O -MTase) Non-Structural Protein (Nsp10-16).

Autor: Benjamin MM; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA., Hanna GS; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA., Dickinson CF; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA., Choo YM; Department of Chemistry, University of Malaya, Kuala Lumpur 50603, Malaysia., Wang X; Department of Pharmacy, Lanzhou University, Lanzhou 730000, China., Downs-Bowen JA; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, HSRB-1, Atlanta, GA 30322, USA., De R; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, HSRB-1, Atlanta, GA 30322, USA., McBrayer TR; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, HSRB-1, Atlanta, GA 30322, USA., Schinazi RF; Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, HSRB-1, Atlanta, GA 30322, USA., Nielson SE; Department of Chemistry & Biochemistry, Logan, UT 84322, USA., Hevel JM; Department of Chemistry & Biochemistry, Logan, UT 84322, USA., Pandey P; National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, USA., Doerksen RJ; Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS 38677, USA., Townsend DM; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 70 President St, DD410, Charleston, SC 29425, USA., Zhang J; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 70 President St, DD410, Charleston, SC 29425, USA., Ye Z; Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 70 President St, DD410, Charleston, SC 29425, USA., Wyer S; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA., Bialousow L; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA., Hamann MT; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St, Charleston, SC 29425, USA.; Department of Public Health Sciences, Medical University of South Carolina,135 Cannon St, Charleston, SC 29425, USA.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2024 Oct 28; Vol. 29 (21). Date of Electronic Publication: 2024 Oct 28.
DOI: 10.3390/molecules29215081
Abstrakt: The design and synthesis of antiviral compounds were guided by computationally predicted data against highly conserved non-structural proteins (Nsps) of the SARS-CoV-2 coronavirus. Chromenephenylmethanone-1 (CPM-1), a novel biphenylpyran (BPP), was selected from a unique natural product library based on in silico docking scores to coronavirus Nsps with high specificity to the methyltransferase protein (2'- O -MTase, Nsp10-16), which is responsible for viral mRNA maturation and host innate immune response evasion. To target the 2'- O -MTase, CPM-1, along with intermediate BPP regioisomers, tetrahydrophenylmethanones (TPMs), were synthesized and structurally validated via nuclear magnetic resonance (NMR) data and DP4+ structure probability analyses. To investigate the activity of these BPPs, the following in vitro assays were conducted: SARS-CoV-2 inhibition, biochemical target validation, mutagenicity, and cytotoxicity. CPM-1 possessed notable activity against SARS-CoV-2 with 98.9% inhibition at 10 µM and an EC 50 of 7.65 µM, as well as inhibition of SARS-CoV-2's 2'- O -MTase (expressed and purified) with an IC 50 of 1.5 ± 0.2 µM. In addition, CPM-1 revealed no cytotoxicity (CC 50 of >100 µM) or mutagenicity (no frameshift or base-pair mutations). This study demonstrates the potential of computational modeling for the discovery of natural product prototypes followed by the design and synthesis of drug leads to inhibit the SARS-CoV-2 2'- O -MTase.
Databáze: MEDLINE
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