Development of Nucleoside Derivatives for Nonreceptor Targets

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Hepatitis C (HCV) is the most comon blood-born infection in the United States, where about 35,000 new cases are estimeted to occur each year. There is currently a need for compounds, compositions, and methods that are useful for treating viral infections such as HCV. This project involved novel compounds that inhibit one or more viral proteases. Accordingly, the compounds may be useful for treating viruses, such as HCV. We have explored the structure activity of nucleoside analogues synthesized in our laboratory in models of HCV, including NS5b polymerase assay and the replicon assay. Ring constrained analogues of purine and pyrimidine nucleotides have been explored as inhibitors. Among the modified nucleoside structures that we have recently studied are the methanocarba analogues, in which the ribose moiety is replaced with a rigid, bicyclic carbon ring system. This system contains fused 3-membered and 5-membered rings, and the location of the fusion determines the conformational properties of the riboselike moiety. We recently completed the first synthesis of enantiomerically pure nucleosides in which the riboselike moiety is a (S)-methanocarba ring (constrained in the "South" conformation). This family of derivatives can now be studied in relation to both receptor and nonreceptor targets.