Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous restriction fragment length polymorphism analysis divided variola virus (VARV) strains into two subtypes, one of which included West African and South American isolates. This allowed a dating to be introduced for the first time in estimation of the VARV evolution rate. The results were used to analyze the molecular evolution of the total family Poxviridae. Comparisons of the known nucleotide sequences were performed for the extended conserved central genome region in 42 orthopoxvirus strains and for the eight genes of multisubunit RNA polymerase in 65 viruses belonging to various genera of the family Poxviridae. Using the Bayesian dating method, the mutation accumulation rate of poxviruses was estimated at (1.7-8.8) x 10(-6) nucleotide substitutions per site per year. Computations showed that the modem poxvirus genera started diverging from an ancestral virus more than 200 thousand years ago and that an ancestor of the genus Orthopoxvirus emerged 131 +/- 45 thousand years ago. The other genera of mammalian poxviruses with a low GC content diverged approximately 110-90 thousand years ago. The independent evolution of VARV started 3.4 +/- 0.8 thousand years ago. It was shown with the example of VARV and the monkeypox virus (MPXV) that divergent evolution of these orthopoxviruses started and the West African subtypes of VARV and MPXV were formed as geographical conditions changed to allow isolation of West African animals from other African regions.
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PMID:[Molecular evolution of poxviruses]. 1882 52

Orthopoxviruses include the prototypical vaccinia virus, the emerging infectious agent monkeypox virus, and the potential biothreat variola virus (the causative agent of smallpox). There is currently no FDA-approved drug for humans infected with orthopoxviruses. We screened a diversity-oriented synthesis library for new scaffolds with activity against vaccinia virus. This screen identified a nonnucleoside analog that blocked postreplicative intermediate and late gene expression. Viral genome replication was unaffected, and inhibition could be elicited late in infection and persisted upon drug removal. Sequencing of drug-resistant viruses revealed mutations predicted to be on the periphery of the highly conserved viral RNA polymerase large subunit. Consistent with this, the compound had broad-spectrum activity against orthopoxviruses in vitro. These findings indicate that novel chemical synthesis approaches are a potential source for new infectious disease therapeutics and identify a potentially promising candidate for development to treat orthopoxvirus-infected individuals.
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PMID:Identification of a pyridopyrimidinone inhibitor of orthopoxviruses from a diversity-oriented synthesis library. 2220 44