A study of flavonoid inhibitors against Monkeypox H1 phosphatase

Poxviruses regulate their replication cycle through host phosphorylation pathways, with dual-specific phosphatase H1(DUSP-H1) playing a key role in immune evasion by dephosphorylating STAT1 and inhibiting interferon(IFN) responses. Given its high conservation across orthopoxviruses, it represents a promising antiviral target. This study screened a flavonoid library against DUSP-H1 from monkeypox virus (<i>m</i>DUSP-H1) using a malachite green-based phosphatase assay, identifying Myricetin, (-)-Gallocatechin, Cupressuflavone, (-)-Epigallocatechin gallate, Baicalein, and Herbacetin as potent <i>m</i>DUSP-H1 inhibitors (IC₅₀: 7.07-14.05 μM). Docking analysis revealed key hydrogen bonding interactions between 5,7-hydroxyl groups of the hydroxyflavone backbone and Asp79 and Arg116 of <i>m</i>DUSP-H1, respectively. Additional interactions with Ser23 via the 3'-hydroxyl group seems to enhance binding and effectively blocking the enzyme's active site. These findings align with previous studies on tyrosine phosphatase inhibitors, supporting flavonoids as broad-spectrum viral phosphatase inhibitors. Further structural and pharmacokinetic studies will aid in developing optimised antiviral therapies against monkeypox, variola, and cowpox viruses.