DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES

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 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 Nedd4, 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 Nedd4-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 Nedd4-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 1). We will use BiMC and VLP budding assays to test analogs for their efficacy at specifically inhibiting the PPxY-Nedd4 interaction and subsequent egress of filovirus particles (Aim 2). 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 (Ci67), 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 3). 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.