Broad-Spectrum Small-Molecule Inhibitors Targeting the SAM-Binding Site of Flavivirus NS5 Methyltransferase

• DOI: 10.1021/acsinfecdis.2c00571
• Publication Date: 2023-06-23T05:48:58Z
• Authors: Subodh Kumar Samrat; Qamar Bashir; Yiding Huang; Carl William Trie...; Anil Mathew Thara...; Ran Zhang; Ke Chen; Y. Geoge Zheng; Zhong Li; Hongmin Li
• Keywords: Flavivirus; Zika Virus; Docking (animal)

Flavivirus infections, such as those caused by dengue virus (DENV), West Nile (WNV), yellow fever (YFV), and Zika (ZIKV), pose a rising threat to global health. There are no FDA-approved drugs for flaviviruses, although small number of flaviviruses have vaccines. For or unknown viruses that may appear in the future, it is particularly desirable identify broad-spectrum inhibitors. The NS5 protein regarded one most promising flavivirus drug targets because conserved across flaviviruses. In this study, we used FL-NAH, fluorescent analog methyl donor S-adenosyl methionine (SAM), develop fluorescence polarization (FP)-based high throughput screening (HTS) assay specifically target methyltransferase (MTase), vital enzyme methylates N7 2′-O positions viral 5′-RNA cap. Pilot identified two candidate MTase inhibitors, NSC 111552 288387. compounds inhibited FL-NAH binding DENV3 with low micromolar IC50. Functional assays verified inhibitory potency these molecules activity. Binding studies indicated bound directly similar affinity. Furthermore, showed greatly reduced ZIKV replication cell-based experiments at dosages did not cause cytotoxicity. Finally, docking revealed bind SAM-binding region on MTase, further mutagenesis residues important compounds. Overall, innovative attractive candidates development inhibitors treatment infections.