Highly potent and selective inhibition of bovine viral diarrhea virus replication by γ-carboline derivatives.
Several novel γ-carboline derivatives were identified as selective inhibitors of bovine viral diarrhea virus (BVDV) replication in cell cultures. Among them, 3,4,5-trimethyl-γ-carboline (SK3M4M5M) was the most active against BVDV (Nose strain) in MDBK cells, with a 50% effective concentration of 0.017±0.005μM and a selectivity index of 435. The compound inhibited viral RNA synthesis in a dose-dependent fashion. In a time of drug-addition experiment during a single viral replication cycle, SK3M4M5M lost its antiviral activity when first added at 8h or later after infection, which coincides with the onset of viral RNA synthesis. When selected γ-carboline derivatives, including SK3M4M5M, were examined for their inhibitory effect on the mutant strains resistant to some classes of nonnucleoside BVDV RNA-dependent RNA polymerase inhibitors, all of which target the top of the finger domain of the polymerase, the strains displayed cross-resistance to the γ-carboline derivatives. These results indicate that the γ-carboline derivatives may possibly target a hot spot of the RNA-dependent RNA polymerase. Although SK3M4M5M was highly active against BVDV, the compound proved inactive against hepatitis C virus (HCV) in HCV RNA replicon cells.
Salim
Mohammed T A
MT
Center for Chronic Viral Diseases, Sakuragaoka, Kagoshima University, Japan.
Goto
Yukinori
Y
Hamasaki
Takayuki
T
Okamoto
Mika
M
Aoyama
Hiroshi
H
Hashimoto
Yuichi
Y
Musiu
Simone
S
Paeshuyse
Jan
J
Neyts
Johan
J
Froeyen
Matheus
M
Herdewijn
Piet
P
Baba
Masanori
M
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001912:Bovine Virus Diarrhea-Mucosal Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002417:Cattle; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000737:chemistry* / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D012367:RNA, Viral / Q000096:biosynthesis; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
C556117:3,4,5-trimethyl-gamma-carboline; D000998:Antiviral Agents; D002243:Carbolines; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D012324:RNA-Dependent RNA Polymerase