Hepatitis C virus has infected some 200 million people and is a major threat to human health. The Interferon-alpha/Ribavirin treatments are associated with serious side effects and effective only in few cases. Recently a new class of small drugs was recently discovered that acts against HCV in a new way, binding to the 5' untranslated region of the viral RNA. We reported a novel synthesis and crystal structure of one of these molecules bound to the viral RNA. Our synthetic route offers higher unprecedented access to new and highly optimized drugs against HCV.             Utilizing information gained from the crystal structure, we are able to direct our synthesis towards molecules with a higher probability of increasing potency of our novel compounds. Our library currently has three directions for increasing affinity; make conformationally restricted analogs, change ligands to optimize amine-phosphate bridges, and utilize space in binding pocket for aryl ring substitutions. New compounds will be crystallized with the HCV RNA and the crystal structure along with binding affinity will be obtained. They will also be tested against HCV infected cell lines, allowing us to iteratively refine SAR.             The key innovation of attaching variable side chains late stage in our synthesis, and crystal structure of our compound bound to RNA has afforded us the ability to rapidly synthesize derivatives expected to increase potency. Numerous compounds have already been submitted for assay with more on their way. Initial results from tested compounds have shown good activity against HCV in both binding affinity and cell line studies. Our small library has already shown that not only does conformation restriction play a huge role in compound activity, but chain length may play a huge part as well. Novel compounds will be presented along with assay data which will include both binding affinity and cell line data.

Crystal structure directed library of new small molecules active against the hepatitis c virus (HCV)

248th National Meeting (2014)

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