Imidazo[4,5-c]pyridines inhibit the in vitro replication of the classical swine fever virus and target the viral polymerase.
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-5H-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 microM and for CSFV Wingene (subgroup 2.3) 0.8+/-0.2 microM. Drug-resistant virus was selected by serial passage of the virus in increasing drug-concentration. The BPIP-resistant virus (EC(50): 24+/-4.0 microM) proved cross-resistant with VP32947 [3-[((2-dipropylamino)ethyl)thio]-5H-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.
Vrancken
R
R
Department of Virology, Veterinary and Agrochemical Research Centre, Groeselenberg 99, B-1180 Ukkel, Belgium. rovra@var.fgov.be
Paeshuyse
J
J
Haegeman
A
A
Puerstinger
G
G
Froeyen
M
M
Herdewijn
P
P
Kerkhofs
P
P
Neyts
J
J
Koenen
F
F
D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006692:Classical Swine Fever Virus / Q000187:drug effects* / Q000502:physiology; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects; D021621:Imaging, Three-Dimensional; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
C516398:5-((4-bromophenyl)methyl)-2-phenyl-5H-imidazo(4,5-c)pyridine; D000998:Antiviral Agents; D007093:Imidazoles; D011725:Pyridines; D012367:RNA, Viral; D012324:RNA-Dependent RNA Polymerase