Allosteric inhibitors of Coxsackie virus A24 RNA polymerase. Issue 4 (15th February 2016)

• Record Type: Journal Article
• Authors: Schein, Catherine H.; Rowold, Diane; Choi, Kyung H.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 4(2016)
• Page Start: 570
• Page End: 577
• Publication Date: 2016-02-15
• Subjects: 3Dpol enterovirus RNA polymerase, cleaved from the 3rd viral protein -- 3ABCD where 3B is VPg and 3D the polymerase -- BE binding energy -- CVA Coxsackie virus A -- DENV Dengue virus (a flavivirus that does not use protein priming) -- EV enterovirus -- HCV hepatitis C virus -- PB polymerase buffer -- PV poliovirus -- RdRp RNA dependent RNA polymerase -- SDF structure data file -- VPg viral protein linked to the genome -- VPgpU uridylylated VPg -- polyU polyuridine; Enterovirus RNA polymerase -- Uridylylation mechanism -- Protein-primed RNA synthesis -- Antiviral compounds -- Docking compound libraries -- +-Strand RNA virus -- Coxsackie virus -- Poliovirus; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.12.023
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Coxsackie virus A24 (CVA24), a causative agent of acute hemorrhagic conjunctivitis, is a prototype of enterovirus (EV) species C. The RNA polymerase (3D pol ) of CVA24 can uridylylate thev iralp eptide linked to theg enome (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 (3D pol ), 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 CVA24-3D pol . 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.