Antiviral therapies are urgently needed to control emerging flaviviruses such as dengue, West Nile, and yellow fever. Ribavirin (RBV) has shown activity against flaviviruses in cultured cells, but efficacy in animal models has generally been poor. In a preliminary screen of novel, synthetic 1-β-d-ribofuranosyl-azole analogs, two compounds, 1-β-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR) and 1-β-d-ribofuranosyl-4-ethynyl-[1,3]imidazole (IM18), significantly reduced the replication of dengue virus serotype 2 (DENV-2) in cultured Vero cells. In the current study we demonstrated that the effective concentration 50 (EC50) of ETAR for DENV-2 is substantially lower than both IM18 and RBV. Moreover, ETAR reduced the replication of five additional flaviviruses, including DENV serotypes 1, 3 and 4, Langat virus and Modoc virus, ≥1000-fold relative to untreated controls. Addition of exogenous guanosine to DENV-2 infected cells negated the antiviral effects of both RBV and ETAR, indicating that GTP depletion is a major mechanism of action for both drugs. ETAR represents a promising drug candidate for the treatment of flavivirus infections.
Bibliographical noteFunding Information:
Funding was provided by an NMSU Interdisciplinary Research grant and NIH NM-INBRE 2P20RR01648-09. SG was supported by the NMSU Minority Biomedical Research Support-Research Initiative for Scientific Enhancement (MBRS-RISE) and National Institute of Health Grant ( GM61222 ). We thank Drs. Aravinda de Silva, Alexander Pletnev, Robert Tesh and Stephen Whitehead for providing viruses and other reagents.
- Dengue virus
- Nucleoside analog