Project Grant R41HL160429

LIPID RECEPTOR GPR31 AS A TARGET FOR ANTI-THROMBOTIC AND STROKE THERAPY - DESPITE PREVALENT USE OF ANTI-PLATELET AND ANTI-LIPID THERAPIES, STROKE REMAINS THE THIRD MAJOR CAUSE OF DEATH AND IS THE LEADING CAUSE OF ADULT DISABILITY IN THE US WITH AN ESTIMATED COST IN THE RANGE OF $34 BILLION ANNUALLY. APPROXIMATELY 20% OF THE ANNUAL 795,000 STROKE PATIENTS DIE WITHIN ONE YEAR AND 15-30% ARE PERMANENTLY DISABLED. ANTIPLATELET THERAPY IS MAINLY USED FOR PRIMARY PREVENTION OF ACUTE ISCHEMIC STROKE IN CEREBROVASCULAR DISEASE. BIOACTIVE FATTY ACIDS ARE A NEW CLASS OF MOLECULAR TARGETS THAT HOLD GREAT THERAPEUTIC POTENTIAL BECAUSE OF THEIR DIVERSE ROLE AS SIGNALING MOLECULES THAT REGULATE METABOLISM AND INFLAMMATION. THE OXIDATION OF ARACHIDONIC ACID BY 12-LOX RESULTS IN THE PRODUCTION OF A NUMBER OF BIOACTIVE LIPIDS INCLUDING THE METABOLITE 12(S)-HETE. THE LIPID RECEPTOR GPR31, AN ORPHAN CLASS A GPCR, IS A 12(S)- HETE RECEPTOR RECENTLY SHOWN TO BE INVOLVED IN INFLAMMATORY SIGNALING. WE RECENTLY DISCOVERED THAT GPR31 MEDIATES 12(S)-HETE PROTHROMBOTIC SIGNALING IN PLATELETS AND PROMOTES GLUTAMATE-INDUCED OXIDATIVE TOXICITY NEURONAL CELLS. THEREFORE, WE PROPOSE THAT TARGETING GPR31 MAY PROVIDE A THERAPEUTIC PATH TOWARDS DEVELOPMENT OF A SAFE AND EFFECTIVE ANTIPLATELET THERAPY THAT IS COUPLED WITH SECONDARY NEUROPROTECTIVE EFFECTS FOR MITIGATING AGAINST THE ACUTE NEUROLOGIC SEQUELA OF STROKE TO PROVIDE A MORE EFFECTIVE AND SAFER ALTERNATIVE OPTION OR ADJUNCT TO FIBRINOLYTIC THERAPY. WE HAVE RECENTLY SUCCEEDED IN IDENTIFYING THE FIRST EFFECTIVE GPR31 ANTAGONIST USING OUR CELL-PENETRATING, MEMBRANE-TETHERED, PEPDUCIN TECHNOLOGY TO BE VALIDATED IN THESE PRECLINICAL FEASIBILITY STUDIES AS AN ANTI-PLATELET AND ANTI-STROKE AGENT. WE SHOW HERE THAT THIS I3-LOOP DERIVED GPR31 LIPOPEPTIDE HAS POTENT ANTIPLATELET ACTIVITY AND NEARLY COMPLETELY SUPPRESSES ARTERIAL THROMBOSIS WITHOUT AN EFFECT ON HEMOSTASIS IN MICE. PRELIMINARY DATA WITH THE GPR310 PEPDUCIN INDICATES A SIGNIFICANT REDUCTION IN ATHEROSCLEROTIC LESION BURDEN IN APOE-/- MICE. FURTHERMORE, WE PROVIDE EVIDENCE FOR A DIRECT NEUROPROTECTIVE EFFECT OF THE GPR310 PEPDUCIN ON HT22 NEURONAL CELLS SUBJECTED TO GLUTAMATE MEDIATED OXIDATIVE STRESS. THE GOAL OF THIS PHASE I STTR PROJECT IS TO DEVELOP THE GPR310 PEPDUCIN AS A COLLABORATIVE EFFORT BETWEEN OASIS PHARMACEUTICALS (LEXINGTON, MA), TUFTS MEDICAL CENTER (BOSTON, MA) AND ARONORA (PORTLAND, OR) THAT WOULD PROVIDE KEY EARLY MILESTONES TO ADVANCE THE INITIAL COMMERCIAL DEVELOPMENT OF THE FIRST GPR31 INHIBITOR AS A DUAL ANTIPLATELET, ANTI-STROKE DRUG. THIS FEASIBILITY STUDY WOULD ESTABLISH THE SCIENTIFIC MERIT OF THE PROPOSED PROGRAM BY ACCOMPLISHING THE MAJOR MILESTONES AT THE END OF THE 6 MONTHS OF SAFETY AND EFFICACY IN A STROKE MODEL AND PK/PD CORRELATIONS IN TWO SPECIES.