DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES

DESCRIPTION provided by applicant The ultimate goal of this project is to produce a broad spectrum drug for the treatment of viral infections caused by filoviruses Ebola and Marburg arenaviruses Lassa fever and rhabdoviruses rabies We and others have determined that efficient budding of these emerging human pathogens is dependent on the subversion of host proteins such as Nedd and that PPxY late L budding domains expressed by the matrix proteins of these RNA viruses are critical for such interactions As disruption of virus budding would prevent virus dissemination we will evaluate the ability of small molecule inhibitors to disrupt host Nedd viral PPxY interactions thereby preventing virus budding Our collaborators Drs Michael Lee and Mark Olson USAMRIID Ft Detrick MD have used a known protein structure containing a Nedd PPxY interaction to perform an in silico screen to find potential competitive blockers This effort led to an initial active small molecule hit that ws subsequently improved with additional SAR analog testing The goal of this Phase I STTR grant application is to expand this novel finding by designing and preparing additional analogs to understand SAR and initial ADME properties to support a future drug discovery program in Phase II We will accomplish this by combining the pharmaceutical and medicinal chemistry expertise of the Fox Chase Chemical Diversity Center Inc www fc cdci com FCCDC with the expertise and experience of the Harty Lab at the University of Pennsylvania in the clinical and experimental aspects of antiviral therapy In this SAR development proposal we will design and prepare novel analogs suitable for composition of matter intellectual property protection to understand SAR and increase potency in our assays Aim We will use BiMC and VLP budding assays to test analogs for their efficacy at specifically inhibiting the PPxY Nedd interaction and subsequent egress of filovirus particles Aim In this aim we will also test analogs for their ability to block PPxY mediated budding of live viruses including VSV rabies Ebola Kikwit Marburg Ci and Lassa fever We will seek to understand potential drug property issues by obtaining in vitro absorption distribution metabolism and distribution ADME data and pharmacokinetic PK parameters in mice IV administration for advanced lead compounds Aim As L domain containing matrix proteins are required for efficient virus cell separation of many RNA viruses including filoviruses arenaviruses rhabdoviruses paramyxoviruses and henipaviruses we predict that targeting this virus host interaction domain will serve as the basis for the development of new and powerful broad spectrum antiviral drugs Once we achieve the aims of this proposal we will be ideally positioned to transition into a full drug discovery and development program as part of the more extensive STTR Phase II period where we will seek to find one or more PPxY inhibitors to evaluate in detailed IND directed pharmacokinetic pharmacodynamic and toxicity studies

PUBLIC HEALTH RELEVANCE There is an urgent need to develop antiviral therapy against emerging human RNA viruses that represent potential agents of bioterrorism Marburg Ebola etc We have discovered small molecule compounds that disrupt virus budding that is critical for virus dissemination and disease progression Here the Harty group at the University of Pennsylvania experts in the antiviral technology of this proposal have partnered with the small business Fox Chase Chemical Diversity Center Inc to further develop these broad spectrum antiviral budding inhibitors by using medicinal chemistry live virus budding assays and live cell
imaging techniques