Benjamin, Menny M. and Hanna, George S. and Dickinson, Cody F. and Choo, Yeun-Mun and Wang, Xiaojuan and Downs-Bowen, Jessica A. and De, Ramyani and Mcbrayer, Tamara R. and Schinazi, Raymond F. and Nielson, Sarah E. and Hevel, Joan M. and Pandey, Pankaj and Doerksen, Robert J. and Townsend, Danyelle M. and Zhang, Jie and Ye, Zhiwei and Wyer, Scott and Bialousow, Lucas and Hamann, Mark T. (2024) Cannabinoid-Inspired Inhibitors of the SARS-CoV-2 Coronavirus 2′-O-Methyltransferase (2′-O-MTase) Non-Structural Protein (Nsp10-16). Molecules, 29 (21). p. 5081. ISSN 1420-3049, DOI https://doi.org/10.3390/molecules29215081.
Full text not available from this repository.Abstract
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 mu M and an EC50 of 7.65 mu M, as well as inhibition of SARS-CoV-2's 2 `-O-MTase (expressed and purified) with an IC50 of 1.5 +/- 0.2 mu M. In addition, CPM-1 revealed no cytotoxicity (CC50 of >100 mu M) 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.
| Item Type: | Article |
|---|---|
| Funders: | South Carolina SmartState Program, United States Department of Health & Human Services National Institutes of Health (NIH) - USA (R01AT007318/NCCIH) ; (R01 GM145845/GM/NIGMS) |
| Uncontrolled Keywords: | cannabinoid; coronavirus; SARS-CoV-2; 2 `-O-MTase; methyltransferase; Nsp; non-structural protein; in silico; computational screen; natural products; DP4+NMR analyses |
| Subjects: | Q Science > QD Chemistry R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 20 Feb 2025 02:29 |
| Last Modified: | 20 Feb 2025 02:29 |
| URI: | http://eprints.um.edu.my/id/eprint/47360 |
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