title: 3-(imidazo[1,2-a:5,4-b']dipyridin-2-yl)aniline inhibits pestivirus replication by targeting a hot spot drug binding pocket in the RNA-dependent RNA polymerase.
abstract: The compound 3-(imidazo[1,2-a:5,4-b']dipyridin-2-yl)aniline (CF02334) was identified as a selective inhibitor of the cytopathic effect (CPE) caused by bovine viral diarrhea virus (BVDV) in a virus-cell-based assay. The EC50-values for inhibition of CPE, viral RNA synthesis and the production of infectious virus progeny were 13.0 ± 0.6 μM, 2.6 ± 0.9 μM and 17.8 ± 0.6 μM, respectively. CF02334 was found to be inactive in the hepatitis C subgenomic replicon system. CF02334-resistant BVDV was obtained and was found to carry the N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). Molecular modeling revealed that N264D is located in a small cavity near the fingertip domain of the pestivirus polymerase. CF02334-resistant BVDV was proven to be cross-resistant to BPIP, AG110 and LZ37, inhibitors that have previously been described to target the same region of the BVDV RdRp. CF02334 did not inhibit the in vitro activity of recombinant BVDV RdRp, but did inhibit the activity of BVDV replication complexes. Taken together, these observations indicate that CF02334 likely interacts with the fingertip of the pestivirus RdRp at the same position as BPIP, AG110 and LZ37, which marks this region of the viral polymerase as a "hot spot" for inhibition of pestivirus replication.
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000, Leuven, Belgium.
authors.forename: Simone
authors.initials: S
authors.lastname: Musiu
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, Medicinal Chemistry, B-3000, Leuven, Belgium.
authors.forename: Mathy
authors.initials: M
authors.lastname: Froeyen
authors.affiliation: Université Clermont Auvergne, Université d'Auvergne, IMTV, BP 10448, F-63000, Clermont-Ferrand, France; Inserm, UMR 990, IMTV, F-63005, Clermont-Ferrand, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chezal
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000, Leuven, Belgium. Electronic address: Johan.Neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000, Leuven, Belgium; KU Leuven, Division Animal and Human Health Engineering, Laboratory for Host Pathogen Interactions, Kasteelpark Arenberg 30, 3001, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C000612983:3-(imidazo(1,2-a-5,4-b')dipyridin-2-yl)aniline; D000814:Aniline Compounds; D006575:Heterocyclic Compounds, 3-Ring; D012324:RNA-Dependent RNA Polymerase
keywords: 3-(imidazo[1,2-a:5,4-b′]dipyridin-2-yl)aniline; Bovine viral diarrhea virus; RNA-dependent RNA polymerase