Despite prevalent use of anti-platelet and anti-lipid therapies, stroke remains the third major cause of deathand is the leading cause of adult disability in the US with an estimated cost in the range of $34 billionannually. Approximately 20% of the annual 795,000 stroke patients die within one year and 15-30% arepermanently disabled. Antiplatelet therapy is mainly used for primary prevention of acute ischemic stroke incerebrovascular disease. Bioactive fatty acids are a new class of molecular targets that hold greattherapeutic potential because of their diverse role as signaling molecules that regulate metabolism andinflammation. The oxidation of arachidonic acid by 12-LOX results in the production of a number of bioactivelipids 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 GPR31mediates 12(S)-HETE prothrombotic signaling in platelets and promotes glutamate-induced oxidativetoxicity in neuronal cells. Therefore, we propose that targeting GPR31 may provide a therapeutic pathtowards development of a safe and effective antiplatelet therapy that is coupled with secondaryneuroprotective effects for mitigating against the acute neurologic sequela of stroke to provide a moreeffective and safer alternative option or adjunct to fibrinolytic therapy. We have recently succeeded inidentifying the first effective GPR31 antagonist using our cell-penetrating, membrane-tethered, Pepducintechnology to be validated in these preclinical IND-enabling studies as an anti-platelet and anti-strokeagent. We show here that this i3-loop derived GPR31 lipopeptide has potent antiplatelet activity and nearlycompletely suppresses arterial thrombosis without an effect on hemostasis in mice. Preliminary data withthe GPR310 pepducin shows a highly significant reduction in stroke infarct area in mice similar to theprotective effect of Gpr31-deficiency. Furthermore, we provide evidence for a direct neuroprotective effect ofthe GPR310 pepducin on HT22 neuronal cells subjected to glutamate mediated oxidative stress. The goalof this Phase 2 STTR project is to develop the GPR310 pepducin as a collaborative effort between OasisPharmaceuticals (Lexington, MA), Tufts Medical Center (Boston, MA) that would provide a robust IND datapackage required to advance the initial commercial development of the first GPR31 inhibitor as a dualantiplatelet, anti-stroke drug. This drug development program would establish the scientific merit of theGPR31 target by accomplishing the major milestones at the end of 2 years of GLP safety/pharmacologyand efficacy in stroke models ± thrombolytic therapy to support a Phase I first-in-human clinical trial.
Public Health Relevance Statement: The only FDA-approved treatment for thrombotic stroke is tissue plasminogen activator, but it is used in less
than 5% of stroke victims with no noted improvement in survival and with no direct neuroprotective effects.
Here, we provide a blueprint for developing the first GPR31 inhibitor as an effective antiplatelet therapy that
provides secondary neuroprotective effects for mitigating against the acute neurologic sequela of stroke for
a potentially more effective and safer alternative option or adjunct to fibrinolytic therapy in this area of high
unmet medical need.
Project Terms: <21+ years old><12-Lipoxygenase> | | | | 