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Structural effects on the phosphorylation of 3-substituted 1-beta-D-ribofuranosyl-1,2,4-triazoles by human adenosine kinase

Department of Chemistry and Biochemistry, MSC 3C, New Mexico State University, Las Cruces, NM 88003, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 07/2007; 17(11):3203-7. DOI: 10.1016/j.bmcl.2007.03.018
Source: PubMed

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.

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    • "The research manifested that this compound represented a promising drug candidate for the treatment of flavivirus infections. Substitution of alkynyl moiety by other electron-withdrawing groups such as nitro or acetyl one decreased the antiviral efficacy sharply (Kumarapperuma et al., 2007). Several 1-benzyl-1H-1,2,3-triazoles attached to different carbohydrate templates were investigated for their anti-HIV activities. "
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    • "We have previously synthesized a panel of 21 novel nucleoside analogs, some based on the structure of RBV (Chung et al., 2008; Kumarapperuma et al., 2007). One of these compounds, 1-β-D-ribofuranosyl-3-ethynyl-[1] [2] [4]triazole (ETAR) inhibited replication of Hantaan and Andes virus with effective concentration 50 (EC 50 ) values of 10 and 4.4 μM, respectively (Chung et al., 2008). "
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    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.
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    • "Focusing on the heterocyclic-␤-riboside structure, we prepared a diverse series of 3-substituted 1,2,4-triazole-␤-ribosides, including isosteric derivatives of RBV and linkage isomers that exhibit altered hydrogen-bonding capacity. We have previously evaluated representative compounds from this series as substrates for adenosine kinase (Kumarapperuma et al., 2007). Herein, we describe the antiviral activity of 1-␤-d-ribofuranosyl-3-ethynyl-[1] [2] [4]triazole (ETAR, Fig. 1) against 4 viruses, HTNV, ANDV, CCHFV, and RVFV. "
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    ABSTRACT: There are no FDA approved drugs for the treatment of hemorrhagic fever with renal syndrome (HFRS), a serious human illnesses caused by hantaviruses. Clinical studies using ribavirin (RBV) to treat HFRS patients suggest that it provides an improved prognosis when given early in the course of disease. Given the unique antiviral activity of RBV and the lack of other lead scaffolds, we prepared a diverse series of 3-substituted 1,2,4-triazole-beta-ribosides and identified one with antiviral activity, 1-beta-d-ribofuranosyl-3-ethynyl-[1,2,4]triazole (ETAR). ETAR showed an EC(50) value of 10 and 4.4 microM for Hantaan virus (HTNV) and Andes virus, respectively. ETAR had weak activity against Crimean Congo hemorrhagic fever virus, but had no activity against Rift Valley fever virus. Intraperitoneally delivered ETAR offered protection to suckling mice challenged with HTNV with a approximately 25% survival at 12.5 and 25mg/kg ETAR, and a MTD of 17.1+/-0.7 days. ETAR was phosphorylated in Vero E6 cells to its 5'-triphosphate and reduced cellular GTP levels. In contrast to RBV, ETAR did not increase mutation frequency of the HTNV genome, which suggests it has a different mechanism of action than RBV. ETAR is an exciting and promising lead compound that will be elaborated in further synthetic investigations as a framework for the rational design of new antivirals for treatment of HFRS.
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