Optimization of Arenavirus Antivirals

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DESCRIPTION (provided by applicant): Seven distinct arenavirus species have been associated with arenaviral hemorrhagic fevers (AVHF) in humans, with 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 often occurs in clinical settings. AVHF resulting from infection with the Old World arenavirus Lassa, with the exception of Dengue Fever, has the highest human impact of any of the viral hemorrhagic fevers. It 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 the New World arenavirus Junin for which a prophylactic vaccine has been developed. However, no vaccines are available for Lassa or the six other arenaviruses known to infect humans and broad-spectrum vaccines effective against current or emerging arenaviruses are unlikely to be developed. The only available antiviral, ribavirin, has had mixed success in treating severe arenaviral disease and it is associated with significant toxicities. Given the lack of effective treatments and prophylactics, the high mortality rate associated with infection, the potential for both zoonotic and human-to-human transmission, the potential for geographical transplantation, and because large quantities can be propagated in cell culture and transmitted as aerosols, five arenaviruses eliciting severe VHF have been recognized as Category A pathogens; the development of broad spectrum antivirals for the treatment and prophylaxis of VHF is an NIAID priority. Here we propose phase I medicinal chemistry optimization of a lead chemical series for the development of broad spectrum arenavirus antivirals through determination of activity in a variety of BSL2 pseudotype and live virus studies with final confirmation in BSL4 infectious Lassa virus in vitro studies.