Discovery of antiviral inhibitors for the treatment of orthopoxvirus infections

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.