Abstract
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2’-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.
Highlights
The genus Flavivirus in the family Flaviviridae is composed of about 53 arthropod-borne viruses [1,2,3]
Vaccines for humans are currently available for yellow fever virus (YFV), Japanese encephalitis virus (JEV), and Tick-borne encephalitis virus (TBEV) [6, 7], no clinically approved vaccine or antiviral therapy for humans is available for West Nile virus (WNV) and dengue virus (DENV)
A suitable ligand binding pocket for virtual screening (VS) is provided by the crystal structures for S-adenosyl homocysteine (SAH) and 36A ligands bound to the DENV3 MTase (PDB ID: 3P8Z) [39]
Summary
The genus Flavivirus in the family Flaviviridae is composed of about 53 arthropod-borne viruses [1,2,3]. The four serotypes of dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and Tick-borne encephalitis virus (TBEV) are categorized as global emerging pathogens that can cause serious human disease, including meningitis, myelitis, encephalitis, and hemorrhagic disease [4,5,6,7]. Vaccines for humans are currently available for YFV, JEV, and TBEV [6, 7], no clinically approved vaccine or antiviral therapy for humans is available for WNV and DENV. It is a public health priority to develop and improve vaccines and antiviral agents for prevention and treatment of flavivirus infections
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