SAM-dependent viral MTase inhibitors: herbacetin and caffeic acid phenethyl ester, structural insights into dengue MTase

Chikungunya (CHIKV) and dengue (DENV) viruses pose a public health risk and lack antiviral treatment. Structure-based virtual screening of natural MTase substrates library identified herbacetin (HC) and caffeic acid phenethyl ester (CAPE) as potential CHIKV nsP1 and DENV NS5 MTase inhibitors. Binding affinities and MTase inhibition were confirmed using purified proteins. Crystal structure of DENV3 NS5 MTase and CAPE complex revealed CAPE binding at GTP and cap 0 RNA sites. Interestingly, HC and CAPE depleted polyamines, which are crucial for RNA virus replication, and effectively diminished replication with IC₅₀values of ∼13.44 µM and ∼0.57 µM against CHIKV, and ∼7.24 µM and ∼1.01 µM against DENV, respectively. Polyamine addition did not reverse the antiviral effects, suggesting a dual inhibition mechanism.