Journal
ANTIVIRAL RESEARCH
Volume 88, Issue 3, Pages 263-268Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2010.09.013
Keywords
Flavivirus; BVDV; HCV; Carboline; RNA polymerase; Drug-resistance
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Funding
- Japan Science and Technology Agency (JST), Japan
- Egyptian Government
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Several novel gamma-carboline derivatives were identified as selective inhibitors of bovine viral diarrhea virus (BVDV) replication in cell cultures. Among them, 3,4,5-trimethyl-gamma-carboline (SK3M4M5M) was the most active against BVDV (Nose strain) in MDBK cells, with a 50% effective concentration of 0.017 +/- 0.005 mu M 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 8 h or later after infection, which coincides with the onset of viral RNA synthesis. When selected gamma-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 gamma-carboline derivatives. These results indicate that the gamma-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. (C) 2010 Elsevier B.V. All rights reserved.
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