| Autor: |
Benjamin, Menny M., Hanna, George S., Dickinson, Cody F., Choo, Yeun-Mun, Wang, Xiaojuan, Downs-Bowen, Jessica A., De, Ramyani, McBrayer, Tamara R., Schinazi, Raymond F., Nielson, Sarah E., Hevel, Joan M., Pandey, Pankaj, Doerksen, Robert J., Townsend, Danyelle M., Zhang, Jie, Ye, Zhiwei, Wyer, Scott, Bialousow, Lucas, Hamann, Mark T. |
| Zdroj: |
Molecules; Nov2024, Vol. 29 Issue 21, p5081, 17p |
| 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 EC50 of 7.65 µM, as well as inhibition of SARS-CoV-2's 2′-O-MTase (expressed and purified) with an IC50 of 1.5 ± 0.2 µM. In addition, CPM-1 revealed no cytotoxicity (CC50 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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