Discovery of antiviral inhibitors for the treatment of orthopoxvirus infections

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PROJECT SUMMARY Smallpox (caused by variola virus infection) was one of the most destructive diseases in human history, resulting in 300-500 million deaths in the twentieth century alone until it was finally eradicated in 1980. Following elimination of variola virus, global vaccination programs were eventually halted and as a result, most of the world’s population is no longer immunologically protected from smallpox nor does it enjoy cross- protection to other orthopoxviruses. There are two drugs approved for smallpox disease, however, both compounds possess significant limitations. A lack of therapeutic options for treating orthopoxvirus infections continues to expose the population to grave risk from a smallpox bioweapon as well as future zoonotic orthopoxvirus infections. During the course of the Phase I funding period, we will execute a hit finding campaign against a library of >200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against variola virus and other orthopoxviruses with minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.