Allosteric inhibitors of Coxsackie virus A24 RNA polymerase

Catherine H. Schein, Diane Rowold, Kyung H. Choi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3Dpol) of CVA24 can uridylylate the viral peptide linked to the genome (VPg) from distantly related EV and is thus, a good model for studying this reaction. Once UMP is bound, VPgpU primes RNA elongation. Structural and mutation data have identified a conserved binding surface for VPg on the RNA polymerase (3Dpol), located about 20 Å from the active site. Here, computational docking of over 60,000 small compounds was used to select those with the lowest (best) specific binding energies (BE) for this allosteric site. Compounds with varying structures and low BE were assayed for their effect on formation of VPgU by CVA24-3Dpol. Two compounds with the lowest specific BE for the site inhibited both uridylylation and formation of VPgpolyU at 10-20 μM. These small molecules can be used to probe the role of this allosteric site in polymerase function, and may be the basis for novel antiviral compounds.

Original languageEnglish (US)
Pages (from-to)570-577
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number4
DOIs
StatePublished - 2016

Keywords

  • +-Strand RNA virus
  • Antiviral compounds
  • Coxsackie virus
  • Docking compound libraries
  • Enterovirus RNA polymerase
  • Poliovirus
  • Protein-primed RNA synthesis
  • Uridylylation mechanism

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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