Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors

0479566 - BC 2018 RIV US eng J - Journal Article
Valdés, James J. - Butterill, Philip T. - Růžek, Daniel
Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors.
Biochemical and Biophysical Research Communications. Roč. 492, č. 4 (2017), s. 652-658. ISSN 0006-291X. E-ISSN 1090-2104
R&D Projects: GA MZd(CZ) NV16-34238A; GA ČR GB14-36098G
Institutional support: RVO:60077344
Keywords : Analogue * Flaviviridae * Interrogating * Polymerase * Virus * Water
OECD category: Virology
Impact factor: 2.559, year: 2017

The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues. The mechanism how this single mutation causes Flaviviridae viruses to escape nucleoside analogues is not yet known. Given the pivotal position of the serine residue in motif B that supports motif F, we hypothesized the threonine mutation causes alterations in nucleoside exploration within the entry tunnel. Implementing a stochastic molecular software showed the all-atom 2'-C-methylated analogue reaction within the active sites of wild type and serine-threonine mutant polymerases from Hepacivirus and Flavivirus. Compared with the wild type, the serine-threonine mutant polymerases caused a significant decrease of analogue contacts with conserved interrogating residues in motif F and a displacement of metal ion cofactors. The simulations significantly showed that during the analogue exploration of the active site the hydrophobic methyl group in the serine-threonine mutant repels water-mediated hydrogen bonds with the 2'-C-methylated analogue, causing a concentration of water-mediated bonds at the substrate-interacting sites. Collectively, the data are an insight into a molecular escape mechanism by Flaviviridae viruses from 2'-C-methylated nucleoside analogue inhibitors.
Permanent Link: http://hdl.handle.net/11104/0275547