A novel nucleoside analog, 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR), exhibits efficacy against a broad range of flaviviruses in vitro.
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-beta-d-ribofuranosyl-azole analogs, two compounds, 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR) and 1-beta-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 (EC(50)) 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, > or =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.
McDowell
Michael
M
Department of Biology, New Mexico State University, Las Cruces, 88003, USA.
Gonzales
Sarah R
SR
Kumarapperuma
Sidath C
SC
Jeselnik
Marjan
M
Arterburn
Jeffrey B
JB
Hanley
Kathryn A
KA
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D005416:Flavivirus / Q000187:drug effects*; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors; D007093:Imidazoles / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D014709:Vero Cells
C530251:1-ribofuranosyl-3-ethynyl-(1,2,4)triazole; D000998:Antiviral Agents; D007093:Imidazoles; D009705:Nucleosides; D014230:Triazoles; D012254:Ribavirin; D006160:Guanosine Triphosphate