title: Proof of concept for the reduction of classical swine fever infection in pigs by a novel viral polymerase inhibitor.
abstract: 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP) is a representative of a class of imidazopyridines with potent in vitro antiviral activity against pestiviruses including classical swine fever virus (CSFV). This study analysed whether the lead compound, BPIP, was able to reduce virus replication in infected piglets. The compound, administered in feed, was readily bioavailable and was well tolerated. Eight specific-pathogen-free pigs received a daily dose of 75 mg kg(-1) (mixed in feed) for a period of 15 consecutive days, starting 1 day before infection with the CSFV field isolate Wingene. BPIP-treated pigs developed a short, transient viraemia (one animal remained negative) and leukopenia (three animals did not develop leukopenia). Virus titres at peak viraemia (7 days post-infection) were markedly lower (approximately 1000-fold) than in untreated animals (P=0.00005) and the viral genome load in blood was also significantly lower (P<or=0.001) in drug-treated animals than in untreated animals over the entire experiment. At the end of the experiment (day 33), no infectious virus was detectable in the tonsils of BPIP-treated animals, although low levels of viral RNA were detected. The inability to isolate infectious virus from the tonsils indicates that the risk of a persistent CSFV infection is negligible. Further optimization of the antiviral potency and bioavailability of this lead compound may result in molecules completely suppressing virus replication. A potent antiviral could potentially be used as a primary control measure against virus spread in case of an outbreak, in addition to present countermeasures. This study provides the first proof of concept for the prophylaxis/treatment of CSFV infection in pigs.
authors.affiliation: Veterinary and Agrochemical Research Centre, Groeselenberg 99, B-1180 Ukkel, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Vrancken
authors.affiliation: Veterinary and Agrochemical Research Centre, Groeselenberg 99, B-1180 Ukkel, Belgium.
authors.forename: Andy
authors.initials: A
authors.lastname: Haegeman
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Puerstinger
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.affiliation: Gilead Sciences, Drug Metabolism and Pharmacokinetics, 333 Lakeside Drive, Foster City, CA, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
authors.affiliation: Veterinary and Agrochemical Research Centre, Groeselenberg 99, B-1180 Ukkel, Belgium.
authors.forename: Marylène
authors.initials: M
authors.lastname: Tignon
authors.affiliation: Agence Française de Sécurité Sanitaire des Aliments, Unité de Virologie Immunologie Porcines, BP53, F-22440 Ploufragan, France.
authors.forename: Marie-Frédérique
authors.initials: MF
authors.lastname: Le Potier
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Veterinary and Agrochemical Research Centre, Groeselenberg 99, B-1180 Ukkel, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Koenen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006691:Classical Swine Fever / Q000188:drug therapy*; D006692:Classical Swine Fever Virus / Q000187:drug effects*; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007970:Leukopenia / Q000517:prevention & control; D014066:Palatine Tonsil / Q000821:virology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013552:Swine; D019562:Viral Load; D014766:Viremia / Q000517:prevention & control
chemical_list: C516398:5-((4-bromophenyl)methyl)-2-phenyl-5H-imidazo(4,5-c)pyridine; D000998:Antiviral Agents; D007093:Imidazoles; D011725:Pyridines