Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses

Summary: The ultimate goal of this Phase II application is to develop novel small molecule, broad-spectrum therapeutics against viral infections caused by filoviruses, arenaviruses, and other viruses that depend on the PPxY L-domain motif for egress and spread of infection. Some of these viruses, including Ebola (EBOV), Marburg (MARV), and Lassa fever (LAFV) viruses, are highly pathogenic and classified as Category A bioterror pathogens. We and others have determined that efficient budding of these emerging human pathogens depends on the subversion of host proteins, such as neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4), by PPxY L-domains in the matrix proteins of these RNA viruses. The identification and development of small molecule inhibitors that interfere with these virus-host interactions should effectively block virus egress, disease progression, and transmission. In these efforts we have discovered several chemical series of small molecule inhibitors of the host Nedd4/virus PPxY complex important for viral egress which led to one analog possessing proof of concept in vivo activity in a Marburg virus challenged mouse model. As FDA approved therapeutic agents for the treatment of these most of these viral infections are not available, our identification of virus-host inhibitors that may prevent virus spread will fill a significant unmet need. Moreover, these inhibitors will be broad-spectrum, and therefore will likely be effective against newly emerging viruses as well as viral variants. As described below, we will use a rigorous multifaceted approach to identify, develop, and validate PPxY budding inhibitors identified in Phase I as potent, broad-spectrum antivirals. The goal of this Phase II STTR grant application is to optimize our lead inhibitors of VP40 PPxY-Nedd4 interactions to generate full- fledged predevelopment drug candidates ready for IND directed studies. This will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience in the experimental aspects of antiviral therapy of the Harty Lab at the University of Pennsylvania. We will realize this goal by optimizing our existing series of inhibitors, exemplified by in vivo active FC-10696, for improved potency and oral drug properties (Aim 1), evaluating new compounds based on two potent series for their ability to specifically inhibit PPxY-Nedd4 interactions and subsequent VLP and surrogate virus egress (Aim 2), identifying compounds having suitable drug properties and selectivity using in vitro and in vivo ADMET evaluation (Aim 3), and evaluating compounds for their antiviral efficacy against authentic BSL-4 viruses in vitro and in vivo (Aim 4).