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Principal Investigator: ROBERT A DAVEY
Organization: PURDUE UNIVERSITY
Fiscal Year: 2020
Award: $704,383
Funding agency: National Institute of Allergy and Infectious Diseases
A research team from Purdue University and Texas Biomedical Research Institute is in pursuit of important new approaches to validate the host V-ATPase. The project goal to define antiviral drug leads for diseases caused by Ebola and Marburg filoviruses. Many viral pathogens bind to specific factors of host cells to penetrate the plasma member inside vesicles called endosomes. However, entry of the virus to the host cells requires escape from these vesicles. A majority of these viruses utilize the low pH of late endosomes to trigger the final steps in viral entry. Since the acidification of endosomes depends on vacuolar H(+)-ATPases (V-ATPases), inhibiting this pump interferes with entry of a wide range of viruses. Thus, the host V-ATPase represents a truly broad-spectrum target for antiviral drugs. While feasible, there are challenges for developing antiviral drugs that targets host factors like V-ATPase because of the potential risk of toxicity to non-infected cells and tissues. The approach used in this project directly addresses this challenge which will apply discovery and pharmaceutical technologies to achieve selectivity of drug action. The project team brings significant expertise to the challenges for discovery and development of host-targeted antiviral therapeutics. Efforts will integrate chemistry and biochemistry of natural-product V-ATPase inhibitors, viral-host entry pathways, Ebola and Marburg animal disease models in BSL4 facility, in vitro and in vivo ADME-pharmacokinetics, and toxicology. Currently, there is a lack of suitable in vivo chemical probes available to test safety and efficacy of pharmaceutical interventions targeting V-ATPase. The objectives for this five-year project are to: a) qualify a class of selective chemical inhibitors for V-ATPase suitable for in vivo antiviral efficacy testing, and b) identify a new drug lead candidate targeting V-ATPase function during the viral entry process for Ebola and Marburg filoviruses. These complementary objectives will impact the prospects and precise strategy for developing antiviral therapies to treat unmet needs.
Terms: <Address><Affect><Animal Disease Models><Animal Model><Animal Models and Related Studies><Antiviral Agents><Antiviral Drugs><Antiviral Therapy><Antivirals><Assay><BSL-4 facility><BSL4 facility><Binding><Bioassay><Bioavailability><Biochemical><Biochemistry><Biologic Assays><Biologic Availability><Biological Assay><Biological Availability><Biological Chemistry><Biomedical Research><Blood Plasma><Body Tissues><Boston><Category A pathogen><Category A priority pathogen><Cell Body><Cell model><Cells><Cellular Assay><Cellular model><Chemicals><Chemistry><Data><Dendritic Cells><Development><Disease><Disorder><Dose><Drug Kinetics><Drug Targeting><Drugs><EBOV><Ebola><Ebola virus><Endosomes><Filoviridae><Filoviridae Infections><Filovirus><Formulation><Frankfurt-Marburg Syndrome Virus><Funding Mechanisms><Goals><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Host Factor><Host Factor Protein><Human><In Vitro><Infection><Integration Host Factors><Intervention><Intervention Strategies><Investigators><Ion Channel><Ionic Channels><Lactone Compound><Lactones><Lead><Liver Cells><Marburg><Marburg virus><Measures><Medication><Medicinal Chemistry><Membrane Channels><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Natural Products><Oral><Outcome><Pathway interactions><Pb element><Pharmaceutic Chemistry><Pharmaceutic Preparations><Pharmaceutic Technology><Pharmaceutical Agent><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmaceutical Technology><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Pharmacology><Pharmacy Technology><Phenotype><Physiologic Availability><Plasma><Plasma Serum><Population><Primary Infection><Process><Property><Pump><Receptosomes><Relative Risks><Research><Research Institute><Research Personnel><Researchers><Reticuloendothelial System, Serum, Plasma><Retroviridae><Retroviruses><Risk><Safety><Selection Criteria><Series><Site><Structure><Testing><Texas><Therapeutic><Tissues><Toxic effect><Toxicities><Toxicology><Translating><Translations><Universities><V-ATPase><V-type ATPase><Validation><Veiled Cells><Vesicle><Viral><Virus><Virus Replication><Virus-Retrovirus><analog><anti-viral agents><anti-viral drugs><anti-viral efficacy><anti-viral therapy><anti-virals><antiviral efficacy><base><biosafety level 4 facility><cell assay><design><designing><developmental><drug action><drug development><drug/agent><ebolavirus><efficacy study><efficacy testing><filovirus infections><heavy metal Pb><heavy metal lead><improved><in vitro testing><in vivo><in vivo Model><inhibitor><inhibitor/antagonist><insight><interventional strategy><late endosome><lead candidate><macrophage><member><model of animal><model organism><mouse model><murine model><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-human primate><nonhuman primate><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><pathogenic virus><pathway><pre-clinical><preclinical><prevent><preventing><safety testing><small molecule><vacuolar ATPase><vacuolar H+-ATPase><vacuolar membrane H(+)-ATPase><viral infectious disease treatment><viral multiplication><viral pathogen><viral replication><virus multiplication>