Structural effects on the phosphorylation of 3-substituted 1-beta-D-ribofuranosyl-1,2,4-triazoles by human adenosine kinase.
ABSTRACT The conversion of ribavirin to the monophosphate by adenosine kinase is the rate-limiting step in activation of this broad spectrum antiviral drug. Variation of the 3-substituents in a series of bioisosteric and homologated 1-beta-D-ribofuranosyl-1,2,4-triazoles has marked effects on activity with the human adenosine kinase, and analysis of computational descriptors and binding models offers insight for the design of novel substrates.
- SourceAvailable from: Jeffrey B Arterburn[Show abstract] [Hide abstract]
ABSTRACT: 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.Antiviral research 04/2010; 87(1):78-80. · 3.61 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Emergence of severe viral infections in recent years and limited availability of antiviral chemotherapeutic agents for prevention and treatment of these infections are among the most common causes of human illness and death. Therefore, there is an urgent need to develop antiviral drugs that have a potentially critical role in the prevention and treatment of various fatal and debilitating viral infections. Triazole derivatives occupy a pivotal position in modern medicinal chemistry and several have found applications as medicines. A large volume of research has been carried out on triazole and their derivatives for antiviral activity and pharmacological importance of this scaffold has been well established. This review is primarily addressed to description of the recent advances in the synthesis and evaluation of triazole derivatives as antiviral agents which may facilitate the development of more potent and effective antiviral agents.Mini Reviews in Medicinal Chemistry 10/2010; 11(1):84-96. · 2.87 Impact Factor
Dataset: Antiviral triazole Rajeev