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Updated: Jan 8, 2026
High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Mechanistic Insights Into the Inhibition of Dengue Virus NS5 Methyltransferase by Herbacetin
Mandar Bhutkar1, Shalja Verma1, Vishakha Singh1
1Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India.
Abstract:
Herbacetin (HC) is a naturally occurring flavonoid compound with a dual antiviral mechanism. It inhibits the polyamine biosynthetic pathway and targets the methyltransferase (MTase) enzyme of both the dengue virus (DENV) and chikungunya virus (CHIKV). However, the detailed inhibition mechanism of DENV-3 non-structural protein (NS5) MTase by HC remains unclear. This study provides structural insights into the inhibition mechanism of HC by analyzing the crystal structure of DENV-3 NS5 MTase complexed with HC and S-adenosyl-L-homocysteine. Structural analysis revealed that HC binds to the Cap 0-RNA site near the GTP binding site in the DENV-3 NS5 MTase. Additionally, the fluorescence polarization assay demonstrated that HC inhibits GTP binding with an inhibition constant (Ki) value of ~0.43 μM. This is one of the first studies that identify an inhibitor that targets the conserved RNA-binding region of NS5 MTase, suggesting its potential as a highly effective scaffold for broad-spectrum antiviral agents against orthoflaviviruses.
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