title: A novel, highly selective inhibitor of pestivirus replication that targets the viral RNA-dependent RNA polymerase.
abstract: We report on the highly potent and selective antipestivirus activity of 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP). The 50% effective concentration (EC50) for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect formation was 0.04 +/- 0.01 microM. Comparable reduction of viral RNA synthesis (EC50 = 0.12 +/- 0.02 microM) and production of infectious virus (EC50= 0.074 +/- 0.003 microM) were observed. The selectivity index (ratio of 50% cytostatic concentration/EC50) of BPIP was approximately 2,000. BPIP was inactive against the hepatitis C virus subgenomic replicon and yellow fever virus but demonstrated weak activity against GB virus. Drug-resistant mutants were at least 300-fold less susceptible to BPIP than wild-type virus; showed cross-resistance to N-propyl-N-[2-(2H-1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine (VP32947), and carried the F224S mutation in the viral RNA-dependent RNA polymerase (RdRp). When the F224S mutation was introduced into an infectious clone, the drug-resistant phenotype was obtained. BPIP did not inhibit the in vitro activity of recombinant BVDV RdRp, but did inhibit the activity of replication complexes (RCs). Computational docking revealed that F224 is located at the top of the finger domain of the polymerase. Docking of BPIP in the crystal structure of the BVDV RdRp revealed aromatic ring stacking, some hydrophobic contacts, and a hydrogen bond. Since two structurally unrelated compounds, i.e., BPIP and VP32947, target the same region of the BVDV RdRp, this position may be expected to be critical in the functioning of the polymerase or assembly of the RC. The potential of BPIP for the treatment of pestivirus and hepacivirus infections is discussed.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Eric
authors.initials: E
authors.lastname: Mabery
authors.forename: Nina
authors.initials: N
authors.lastname: Boddeker
authors.forename: Robert
authors.initials: R
authors.lastname: Vrancken
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Israrul H
authors.initials: IH
authors.lastname: Ansari
authors.forename: Hélène
authors.initials: H
authors.lastname: Dutartre
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Laura H V G
authors.initials: LH
authors.lastname: Gil
authors.forename: Carine
authors.initials: C
authors.lastname: Letellier
authors.forename: Robert
authors.initials: R
authors.lastname: Lanford
authors.forename: Bruno
authors.initials: B
authors.lastname: Canard
authors.forename: Frank
authors.initials: F
authors.lastname: Koenen
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerkhofs
authors.forename: Ruben O
authors.initials: RO
authors.lastname: Donis
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
authors.forename: Julia
authors.initials: J
authors.lastname: Watson
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Gerhard
authors.initials: G
authors.lastname: Puerstinger
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D030241:Diarrhea Virus 1, Bovine Viral / Q000187:drug effects; D024882:Drug Resistance, Viral; D007093:Imidazoles / Q000494:pharmacology; D007928:Lethal Dose 50; D009154:Mutation; D010576:Pestivirus / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C516398:5-((4-bromophenyl)methyl)-2-phenyl-5H-imidazo(4,5-c)pyridine; D000998:Antiviral Agents; D007093:Imidazoles; D011725:Pyridines; D012367:RNA, Viral; D014227:Triazines; D012324:RNA-Dependent RNA Polymerase