Research Project
9707746
The ultimate goal of this Phase I application is to develop novel small molecule, broad-spectrum therapeutics against viral infections caused by filoviruses that depend on the PPxY L-domain motif for virus egress and spread of infection. Ebola (EBOV) and Marburg (MARV) viruses are highly pathogenic and classified as Category A, high-priority bioterror pathogens. As there are no commercially available therapeutic agents for the treatment of these viral infections, our identification of virus-host inhibitors that may prevent virus spread will fill a significant unmet need. Indeed, development of such inhibitors is becoming more urgent, as EBOV can cross the blood-brain barrier and re-emerge months later in the CNS, semen, and other immunologically privileged sites that are inaccessible to antibody therapy. Our proposed anti-viral therapeutic that targets EBOV and MARV is expected to be used for treatment of infected individuals as well as in prophylactic treatment of soldiers, healthcare workers, or others at high risk. We postulate that emergency administration of such an antiviral therapeutic during an outbreak would inhibit virus dissemination in infected individuals and reduce the efficacy of infection in newly exposed individuals, thus slowing disease progression, allowing for more effective viral clearance by the immune system, and preventing further viral transmission. As these host-oriented inhibitors are broad-spectrum, they are likely to be effective against newly emerging viruses as well as viral variants. Indeed, we predict that targeting a virus-host interaction necessary for efficient virus egress and dissemination will greatly diminish or eliminate the occurrence of drug resistant viral mutations and may lead to a paradigm shift in the search for better antiviral drugs. Importantly, as these virus-host interactions represent a common mechanism in a range of RNA viruses, we predict that they represent an Achilles? heel in the life cycle of many RNA virus pathogens. Our aims include 1) optimization of current lead inhibitors to achieve adequate drug properties for proof of concept testing in Ebola and Marburg mouse models; 2) evaluate compounds for their ability to specifically inhibit PPxY-Nedd4 interaction and subsequent virus egress;3) evaluate ADME/PK properties for compounds meeting criteria of Specific Aim 2; 4) evaluate lead inhibitors using in vitro and in vivomodels of authentic hemorrhagic fever viruses. Our goals will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center (FCCDC) with the expertise and experience of the Harty Lab at the University of Pennsylvania in the experimental aspects of antiviral therapy, and with the small animal model and filovirus expertise of the BSL-4 laboratory of Dr. Robert Davey at Texas Biomedical Research Institute.
