Drug-induced hepatotoxicity is the most common cause of acute liver injury, a potentially fatal condition for which current therapies are limited o supportive care and liver transplantation. It is also the most common reason that potentially life-saving drugs are abandoned during development and never reach patients. Heprotech Inc. was formed to develop liver-safe pharmaceuticals and treatments for drug-induced liver injury. We recently discovered a novel role for gap junction-dependent communication in the propagation of drug-induced liver injury and have identified a tool compound that interferes with this pathway. Heprotech now seeks funding to support a drug discovery program that will use high throughput screening of small molecule libraries to develop a portfolio of therapeutic compounds that will serve as first-in-class hepatoprotectants. The overall goal of this project is to developa high throughput screening assay that will identify a novel class of drugs that will be developed to treat and prevent drug-induced liver injury. This grant focuses on discovery of inhibitors of connexin 32 (Cx32), a liver-specific gap junction protein that we recently demonstrated to be essential for propagating drug-induced liver injury. The project's specific aims are: 1) To develop a Cx32-containing liposome reporter system for measuring gap junction permeability, 2) To establish a reproducible high throughput screening assay using the Cx32 liposome reporter system, and 3) To screen for inhibitors of Cx32 hemichannels and evaluate their ability to limit propagation of cellular injury in a live cell-based secondary screen. The anticipated outcome of this effort is a collection of promising potent Cx32 inhibitors that can be further developed through rigorous preclinical studies during phase II of this SBIR program.
Public Health Relevance Statement: Public Health Relevance: Heprotech Inc. develops liver-protective therapeutics for the treatment of acute liver diseases such as drug-induced liver injury. Drug hepatotoxicity is the most common cause of acute liver injury, a potentially fatal condition for which current therapies are often limited to supportive care and liver transplantation. It is also the most common reason that efficacious and potentially life- saving drugs are abandoned during development and never reach patients. Scientists at Heprotech recently discovered a novel role for hepatocyte gap junction intercellular communication in the propagation of drug-induced liver injury, and demonstrated that inhibition of this gap junction communication pathway limits liver injury and inflammation. Heprotech is actively searching for small molecule compounds that inhibit various stages of this communication pathway, and developing these inhibitors for clinical use in treating acute drug- induced liver injury. We now seeks funding to support the establishment of a global drug discovery program that will use multiple high throughput screening assays to identity a portfolio of small molecule gap junction inhibitors to serve as first-in-class hepatoprotectants.
Project Terms: Accounting; Acetaminophen; Acute; acute drug induced liver toxicity; acute liver disease; Acute Liver Failure; Affect; base; Biochemical; Biological Assay; cell injury; Cells; Cessation of life; Chemicals; Clinical; Coculture Techniques; Collection; Communication; connexin 32; Connexins; Coupled; Cytosol; Development; Dose-Limiting; drug discovery; Drug Industry; Drug toxicity; Funding; Gap Junctions; Goals; Grant; Hepatocyte; Hepatoprotective Agent; Hepatotoxicity; high throughput screening; Hour; Human; inhibitor/antagonist; intercellular communication; Life; Liposomes; Liver; Liver Failure; liver inflammation; liver injury; liver transplantation; Marketing; Measures; Mediator of activation protein; Morbidity - disease rate; Mortality Vital Statistics; Mus; novel; Organ; Organ failure; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physicians; preclinical study; Preclinical Testing; prevent; Process; programs; Proteins; proteoliposomes; public health medicine (field); public health relevance; Reporter; response; Role; Safety; Scientist; Signal Transduction; Small Business Innovation Research Grant; small molecule; small molecule libraries; Specificity; Staging; Supportive care; System; Therapeutic; therapy development; tool; Toxic effect
