Development of mitoNEET agonists for the treatment of stroke

ABSTRACT Stroke is the fifth leading cause of death and the leading cause of disability in the United StatesThere remains a critical need for innovative therapeutic approaches that can successfully prevent or reverse brain injury following strokeDysfunction of the mitochondrial biochemistry following ischemic stroke and reperfusion injury contributes to significant neuronal cell losshoweverthe development of therapeutics targeting mitochondrial function for stroke patients are lackingMitochondrial dysfunction plays a central role in the neuronal cell death seen in ischemia reperfusion injurybut has not yet been fully investigated as drug targetIn this projectwe are investigating novel mitochondrial protein mitoNEET as therapeutic drug target of mitochondrial function in strokeMitoNEET is a newly discovered protein that regulates mitochondrial bioenergeticsWe developed a first inclass mitoNEET agonist NLwhich showed significant tissue protection after transient ischemia in the brainThe objectives of this proposal are to evaluate a recently discovered mitochondrial proteinmitoNEETas an effective therapeutic approach for the pharmacological treatment of strokeMitoNEETCISDgeneregulates mitochondrial bioenergetics capacity where it functions as redox sensorOur central hypothesize is that ligands selective for mitoNEET will protect brain tissue from hypoxia induced reperfusion injuryOur approach involves state of the art medicinal chemistry approaches to identify novel drug candidates and develop a structure activity relationshipIn our first aimwe will develop potent and selective mitoNEET ligands with drug like propertiesIn the second aimwe will optimize the formulation of the mitoNEET ligands for in vivo studiesThese compounds and drug delivery systems will have far reaching implication for developing neuroprotective medications as a treatment strategy for limiting the mitochondrial contribution to cell loss in the clinical setting in the treatment of stroke patients PROJECT NARRATIVE Cerebral ischemic stroke is a leading cause of mortality and disability in the United StatesThis proposal will develop a novel class of therapeutic agents that act at the mitochondria to prevent the loss of neuronal function following strokeThese novel compounds provide a new pharmaceutical approach for improving stroke outcomes in patients