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.
Public Health Relevance Statement: 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, our team of experts will further develop these broad-spectrum antiviral budding inhibitors by using medicinal chemistry, live virus budding assays, and small animal models of infection.
Project Terms: inhibitor/antagonist; inhibitor; Antiviral Agents; anti-virals; anti-viral drugs; anti-viral agents; Antivirals; Antiviral Drugs; Biological Assay; Biologic Assays; Bioassay; Assay; Biomedical Research; Blood - brain barrier anatomy; Hemato-Encephalic Barrier; Blood-Brain Barrier; Cell Culture Techniques; cell culture; Pharmaceutical Chemistry; Pharmaceutic Chemistry; Medicinal Chemistry; Complement; Complement Proteins; Disease; Disorder; Disease Outbreaks; Outbreaks; Pharmaceutical Preparations; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Ebola virus; ebolavirus; Ebola; EBOV; Emergency Situation; Emergencies; Foxes; Goals; Health Personnel; treatment provider; medical personnel; healthcare personnel; health workforce; health provider; health care worker; health care personnel; Healthcare worker; Healthcare Providers; Health Care Providers; Human; Modern Man; Immune system; allergic/immunologic organ system; allergic/immunologic body system; In Vitro; Infection; Laboratories; Lassa Fever; Lead; heavy metal lead; heavy metal Pb; Pb element; Life Cycle Stages; life course; Life Cycle; Frankfurt-Marburg Syndrome Virus; Marburg virus; Marburg; Liver Microsomes; Mus; Murine; Mice Mammals; Mice; Mutation; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Pennsylvania; Drug Kinetics; Pharmacokinetics; Plasma Proteins; Proteins; Research Institute; RNA Viruses; Seminal fluid; Semen; Solubility; Testing; Texas; Time; Universities; Vesicular stomatitis Indiana virus; Vesicular Stomatitis Virus; VSV; Virus Diseases; virus-induced disease; virus infection; viral infection; Viral Diseases; Virus; General Viruses; Work; Mediating; base; improved; Prophylaxis; Prophylactic treatment; Site; Phase; Variation; Variant; Series; Arenavirus group; Arenaviridae; Arenavirus; Filoviridae; Filovirus; Chemicals; Individual; bound protein; Protein Binding; Ligand Binding Protein Gene; Ligand Binding Protein; Binding Proteins; Disease Progression; analog; viral infectious disease treatment; anti-viral therapy; Antiviral Therapy; antibody-based treatment; antibody-based therapeutics; antibody treatment; antibody based therapies; Antibody Therapy; Therapeutic; Therapeutic Agents; Metabolic; immune clearance; immune elimination; programs; Scientist; Oral; Viral; Soldier; meetings; experience; recombinant virus; virus identification; Animal Model; model organism; model of animal; Animal Models and Related Studies; virus host interaction; aqueous; Toxic effect; Toxicities; novel; Categories; hemorrhagic fever virus; Positioning Attribute; Position; Pharmacodynamics; Property; Bioterrorism; Biological Terrorism; drug discovery; Lassa fever virus; Pathogenicity; prevent; preventing; Virus-like particle; viruslike particle; virus-like nanoparticles; small molecule; Data; Mammalian Cell; in vivo; Immunologically; Immunological; Immunologic; Immunochemical Immunologic; Immunologics; developmental; Development; preclinical; pre-clinical; Drug resistant viral; drug resistant virus; pathogen; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; murine model; mouse model; therapeutic target; high risk; protective efficacy; efficacy testing; small molecule therapeutics; virus transmission; viral transmission; lead optimization; in vivo testing; in vivo evaluation
