Project Grant R01AI160246

IND-ENABLING STUDIES FOR ARENAVIRUS PRECLINICAL CANDIDATE - SUMMARY ARENAVIRUSES COMPRISE A DIVERSE FAMILY. SEVERAL SPECIES ARE ASSOCIATED WITH SEVERE ARENAVIRAL HEMORRHAGIC FEVER (AVHF) IN HUMANS. HUMAN INFECTION WITH ARENAVIRUSES TYPICALLY OCCURS THROUGH CONTACT WITH MATERIALS CONTAMINATED WITH THE EXCRETIONS OF AN INFECTED RODENT ALTHOUGH DIRECT HUMAN- TO-HUMAN TRANSMISSION MAY OCCUR IN CLINICAL SETTINGS. AVHF RESULTING FROM INFECTION WITH THE OLD WORLD ARENAVIRUS LASSA IS ESTIMATED TO CAUSE OVER 300,000 ANNUAL INFECTIONS IN WESTERN AFRICA, OF WHICH 15-20% OF HOSPITALIZED PATIENTS DIE WHILE SURVIVORS OFTEN SUFFER PERMANENT SEQUELAE. THE INTRAVENOUS ADMINISTRATION OF THE NONSPECIFIC ANTIVIRAL AGENT HAS BEEN ADOPTED RIBAVIRIN (OFF-LABEL) FOR LASSA VIRUS INFECTIONS IN WESTERN AFRICA. HOWEVER, IT HAS BEEN SHOWN TO PROVIDE LIMITED EFFICACY AND A SIGNIFICANT RISK FOR SERIOUS SIDE EFFECTS INCLUDING THROMBOCYTOPENIA AND ANEMIA. GIVEN THE LIMITED TREATMENT AND PROPHYLACTIC OPTIONS, THE MORTALITY/MORBIDITY RATE, THE POTENTIAL FOR BOTH ZOONOTIC AND HUMAN-TO-HUMAN TRANSMISSION, GEOGRAPHICAL TRANSPLANTATION AND BIO-WEAPONIZATION SIX ARENAVIRUSES HAVE BEEN RECOGNIZED AS CATEGORY A PATHOGENS. IN ORDER TO PROVIDE A POTENT AND SPECIFIC ANTIVIRAL TO TREAT LASSA AND OTHER ARENAVIRUS HEMORRHAGIC FEVERS HERE WE PROPOSE THE COMPLETION OF IND-ENABLING STUDIES AND ADVANCED NONCLINICAL STUDIES FOR AN ORAL PRECLINICAL CANDIDATE ENTRY INHIBITOR WITH SUB-NANOMOLAR BROAD SPECTRUM ARENAVIRUS ACTIVITY AND DEMONSTRABLE DRUG-LIKE FEATURES THAT EXHIBITS REMARKABLE IN VIVO THERAPEUTIC EFFICACY.