Imidazo[4,5-c]pyridines inhibit the in vitro replication of the classical swine fever virus and target the viral polymerase

• Published in: Antiviral research 2008-02, Vol.77 (2), p.114-119
• Main Authors: Vrancken, R., Paeshuyse, J., Haegeman, A., Puerstinger, G., Froeyen, M., Herdewijn, P., Kerkhofs, P., Neyts, J., Koenen, F.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agent; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Bovine viral diarrhea virus; Cell Line; Classical swine fever virus; Classical swine fever virus - drug effects; Classical swine fever virus - physiology; Diarrhea Viruses, Bovine Viral - drug effects; Drug Resistance, Viral - drug effects; Flaviviridae; Imaging, Three-Dimensional; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazopyridine; Inhibition of classical swine fever virus; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Structure; Pestivirus; Pharmacology. Drug treatments; Polymerase Chain Reaction; Pyridines - chemistry; Pyridines - pharmacology; RNA Replicase - antagonists & inhibitors; RNA Replicase - chemistry; RNA Replicase - genetics; RNA, Viral - genetics; RNA-polymerase; Sequence Analysis, DNA; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2007.09.006

Selective inhibitors of the replication of the classical swine fever virus (CSFV) may have the potential to control the spread of the infection in an epidemic situation. We here report that 5-[(4-bromophenyl)methyl]-2-phenyl-5 H-imidazo[4,5-c]pyridine (BPIP) is a highly potent inhibitor of the in vitro replication of CSFV. The compound resulted in a dose-dependent antiviral effect in PK 15 cells with a 50% effective concentration (EC 50) for the inhibition of CSFV Alfort 187 (subgroup 1.1) of 1.6 ± 0.4 μM and for CSFV Wingene (subgroup 2.3) 0.8 ± 0.2 μM. Drug-resistant virus was selected by serial passage of the virus in increasing drug-concentration. The BPIP-resistant virus (EC 50: 24 ± 4.0 μM) proved cross-resistant with VP32947 [3-[((2-dipropylamino)ethyl)thio]-5 H-1,2,4-triazino[5,6-b]indole], an unrelated earlier reported selective inhibitor of pestivirus replication. BPIP-resistant CSFV carried a T259S mutation in NS5B, encoding the RNA-dependent RNA-polymerase (RdRp). This mutation is located near F224, a residue known to play a crucial role in the antiviral activity of BPIP against bovine viral diarrhoea virus (BVDV). The T259S mutation was introduced in a computational model of the BVDV RdRp. Molecular docking of BPIP in the BVDV polymerase suggests that T259S may have a negative impact on the stacking interaction between the imidazo[4,5-c]pyridine ring system of BPIP and F224.