Cannabinoid-Inspired Inhibitors of the SARS-CoV-2 Coronavirus 2′-O-Methyltransferase (2′-O-MTase) Non-Structural Protein (Nsp10-16)
Document Type
Article
Publication Date
11-1-2024
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.
Keywords
cannabinoid, coronavirus, SARS-CoV-2, 2 `-O-MTase, methyltransferase, Nsp, non-structural protein, in silico, computational screen, natural products, DP4+NMR analyses
Divisions
CHEMISTRY
Funders
South Carolina SmartState Program,United States Department of Health & Human Services National Institutes of Health (NIH) - USA (R01AT007318/NCCIH) ; (R01 GM145845/GM/NIGMS)
Publication Title
Molecules
Volume
29
Issue
21
Publisher
MDPI
Publisher Location
ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND