Project Grant R43AI179443

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.