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 30%. 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 Africa, of which 15-20% 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 6 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.
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.
