Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses

The ultimate goal of this Phase I application is to develop novel small moleculebroad spectrum therapeutics against viral infections caused by filoviruses that depend on the PPxY L domain motif for virus egress and spread of infectionEbolaEBOVand MarburgMARVviruses are highly pathogenic and classified as Category Ahigh priority bioterror pathogensAs there are no commercially available therapeutic agents for the treatment of these viral infectionsour identification of virus host inhibitors that may prevent virus spread will fill a significant unmet needIndeeddevelopment of such inhibitors is becoming more urgentas EBOV can cross the blood brain barrier and re emerge months later in the CNSsemenand other immunologically privileged sites that are inaccessible to antibody therapyOur 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 soldiershealthcare workersor others at high riskWe 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 individualsthus slowing disease progressionallowing for more effective viral clearance by the immune systemand preventing further viral transmissionAs these host oriented inhibitors are broad spectrumthey are likely to be effective against newly emerging viruses as well as viral variantsIndeedwe 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 drugsImportantlyas these virus host interactions represent a common mechanism in a range of RNA viruseswe predict that they represent an Achillesheel in the life cycle of many RNA virus pathogensOur aims includeoptimization of current lead inhibitors to achieve adequate drug properties for proof of concept testing in Ebola and Marburg mouse modelsevaluate compounds for their ability to specifically inhibit PPxY Neddinteraction and subsequent virus egressevaluate ADME PK properties for compounds meeting criteria of Specific Aimevaluate lead inhibitors using in vitro and in vivomodels of authentic hemorrhagic fever virusesOur goals will be accomplished by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity CenterFCCDCwith the expertise and experience of the Harty Lab at the University of Pennsylvania in the experimental aspects of antiviral therapyand with the small animal model and filovirus expertise of the BSLlaboratory of DrRobert Davey at Texas Biomedical Research Institute There is an urgent need to develop antiviral therapy against emerging human RNA viruses that represent potential agents of bioterrorismMarburgEbolaetcWe have discovered small molecule compounds that disrupt virus budding that is critical for virus dissemination and disease progressionHereour team of experts will further develop these broad spectrum antiviral budding inhibitors by using medicinal chemistrylive virus budding assaysand small animal models of infection