Structure-based design and synthesis of nucleoside-triphosphate analogs as new classes of viral polymerase inhibitors

Nucleoside analog inhibitors (NIs) are well-established antiviral drugs. In order to be an active substrate-mimic, an NI must undergo three consecutive phosphorylation steps by three distinct cellular kinases to add α-, β-, and ɤ-phosphates, and the resulting triphosphate form of an NI is the substrate of the viral polymerase. However, the efficiency of phosphorylation steps is a bottleneck for high efficacy of an NI drug. In this project, we will embark on the synthesis of nucleoside triphosphate analogs by modifying pyrophosphate moiety aiming for the discovery of an inhibitor that would directly act as a nucleoside triphosphate analog, and would not require phosphorylation by cellular kinases. A structure-based approach integrating X-ray crystallography and medicinal chemistry will be taken to design and synthesize the compounds for the proposed project. The compounds will be routinely tested against a broad range of viruses in cell-based assays for their antiviral activity and cellular toxicity.