Development of Small Molecule Therapeutics for Emerging Viral Agents

Arenaviruses comprise a diverse group of Old (Africa) and New World (Americas) species. Several species are associated with hemorrhagic fever (HF) with case-fatality rates as high as 30%. Arenaviruses infection typically occurs via the mucosal route through contact with excretions of an infected rodents although direct human-to-human transmission may occur in clinical settings. Lassa arenavirus endemic to Western Africa has significantly higher rate of annual infections (over 300,000) between both Old and New World species. With the exception of a New World Junin virus vaccine, no approved broad-spectrum vaccines or therapeutics are available. We identified a novel broad-spectrum small molecule arenavirus entry inhibitor that exhibits remarkable post-exposure in vivo efficacy including, a guinea pig Lassa model. However, efficacy was evaluated when the virus was inoculated via parenteral routes. Interestingly, current vaccines and monoclonal antibodies when tested in Ebola animal models demonstrate less efficacy when virus is inoculated via aerosol route versus parenteral routes. Because of the potential for aerosol weaponization as well as natural infection via mucosal route, it is important to demonstrate efficacy against arenaviruses through the typical route of infection. Therefore, we propose to evaluate efficacy of our lead candidate in a guinea pig aerosol Lassa model.