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. 2025 Jun;599(11):1531-1555.
doi: 10.1002/1873-3468.70054. Epub 2025 May 12.

Structure-based identification of herbacetin and caffeic acid phenethyl ester as inhibitors of S-adenosylmethionine-dependent viral methyltransferase

Mandar Bhutkar  1 , Amith Kumar  1 , Ruchi Rani  1 , Vishakha Singh  1 , Ankita Saha  1 , Akashjyoti Pathak  1 , Aditi Kothiala  1 , Supreeti Mahajan  1 , Bhairavnath Waghmode  1 , Shalja Verma  1 , Ravi Kumar  1 , Rajat Mudgal  1 , Debabrata Sircar  1 , Pravindra Kumar  1 , Shailly Tomar  1
Affiliations

Structure-based identification of herbacetin and caffeic acid phenethyl ester as inhibitors of S-adenosylmethionine-dependent viral methyltransferase

Mandar Bhutkar et al. FEBS Lett. 2025 Jun.

Abstract

Chikungunya (CHIKV) and dengue (DENV) viruses pose a public health risk and lack antiviral treatments. Structure-based molecular docking of a 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. The crystal structure of DENV 3 NS5 MTase and CAPE complex revealed CAPE binding at viral RNA capping sites. Interestingly, HC and CAPE depleted polyamines crucial for RNA virus replication and decreased viral titer with IC50 values of ~ 13.44 and ~ 0.57 μm against CHIKV, and ~ 7.24 and ~ 1.01 μm against DENV 3, respectively. Polyamine addition did not reverse the antiviral effects, suggesting a dual inhibition mechanism. Impact statement This study reveals the antiviral potential of natural small molecules, Herbacetin (HC) and Caffeic acid phenethyl ester (CAPE) against Dengue and Chikungunya viruses. The molecules deplete polyamine levels and directly inhibit viral methyltransferases. This study opens new avenues for developing antiviral strategies that target both host factors and viral components.

Keywords: Chikungunya virus; Dengue virus; SINV replicon; antiviral assay; crystal structure; polyamine depletion.

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