Optimization of Arenavirus Antivirals

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 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 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 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 BSL pseudotype and live virus studies with final confirmation in BSL infectious Lassa virus in vitro studies PUBLIC HEALTH RELEVANCE Seven distinct arenavirus species have been associated with arenaviral hemorrhagic fevers AVHF in humans five of which cause severe AVHF and have been recognized as NIAID Category A pathogens The development of broad spectrum arenavirus antivirals could provide effective first line therapeutic treatments and or prophylactics