Arenavirus Antiviral Lead Optimization

DESCRIPTION provided by applicant Arenaviruses comprise a diverse family Several species are associated with severe arenaviral hemorrhagic fever AVHF in humans that exhibit case fatality rates as high as 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 annual infections in Africa of which of hospitalized patients die while survivors often suffer permanent sequelae Similar outcomes are observed with Argentine hemorrhagic fever AHF caused by infection with Junin virus A prophylactic vaccine has been developed against JUNV however no vaccines are available against Lassa or the other human hemorrhagic fever arenaviruses and broad spectrum vaccines effective against both current and emerging arenaviruses are unlikely to be developed Ribavirin the only available antiviral can be effective in treating arenavirus infection particularly with IV administration in the first days however there are serious sid effects including thrombocytopenia and anemia Given the limited treatment and prophylactic options the high mortality rate the potential for both zoonotic and human to human transmission and the potential for geographical transplantation and bio weaponization six arenaviruses have been recognized as Category A pathogens Here we propose Phase II optimization of our potent broad spectrum AVHF antiviral lead chemical series Our proposal details a medicinal chemistry lead optimization scheme utilizing in vitro and in vivo efficacy and multispecies ADMET studies against LASV JUNV and other Category A arenaviruses to prioritize advanced leads and identify a preclinical candidate for future IND enabling studies PUBLIC HEALTH RELEVANCE The rapid emergence and dissemination of natural or engineered pathogens causing excessive morbidity and or mortality have the potential for the widespread disruption of world economies and public healthcare systems The goal of this proposal is to optimize our broad spectrum arenavirus antiviral lead chemical series to provide pre clinical candidates with novel therapeutic and human biodefense applications for arenavirus hemorrhagic fevers