Key result
OR2L13 agonist CCF0054500 reduces clot retraction area by ~93% after arterial injury.
Why the study?
Some patients remain at high ischemic risk despite antiplatelet therapy due to drug nonresponsiveness or high residual platelet reactivity, motivating targeting an orphan platelet GPCR from the olfactory receptor family as a novel antithrombotic strategy.
Does the OR2L13-specific agonist CCF0054500 reduce platelet reactivity and arterial thrombosis in preclinical models and human platelets?
Does the OR2L13-specific agonist CCF0054500 reduce platelet reactivity and arterial thrombosis in preclinical models and human platelets?
Activation of the orphan platelet GPCR OR2L13 with a novel agonist reduces platelet reactivity and arterial thrombosis without impairing hemostasis in preclinical models, representing a potential new antithrombotic strategy.
Answers are grounded in this paper and cite their sources.
Should not alter clinical antiplatelet practice; leaves open new therapeutic axis targeting platelet OR2L13 for arterial thrombosis.
BACKGROUND: Despite antiplatelet therapy, some patients remain at high ischemic risk because of drug nonresponsiveness or high residual platelet reactivity). We aimed to target an orphan platelet GPCR (G protein-coupled receptor) from the OR (olfactory receptor) family as a novel antithrombotic strategy. METHODS: Using an engineered reporter cell line expressing human OR2L13, an orphan GPCR implicated in limiting platelet reactivity, we conducted a high-throughput screen of 8000 nonodorant bioactive compounds with counterscreen validation. Subsequent studies assessed platelet function in healthy subjects and patients with coronary artery and peripheral artery disease. Phospho-proteomics revealed key signaling pathways, whereas ex vivo and in vivo assays evaluated the impact of a lead compound on platelet signaling, biomechanics, and thrombosis in both arterial and venous vasculature. RESULTS: We identified 6 OR2L13-specific agonists that suppressed platelet aggregation and α-granule exocytosis through multiple receptors, suggesting a shared downstream mediator. The lead agonist (CCF0054500) phosphorylated platelet HSP27 (heat shock protein 27), disrupting the actin cytoskeleton and reducing clot retraction (clot area, 70.6 versus 5.2; P<0.0001), an effect reversed by HSP27 inhibition. In a murine arterial injury model, CCF0054500 decreased platelet accumulation by 88.9% (P<0.0003) without affecting fibrin generation or hemostasis. In a myocardial infarction model with high residual platelet reactivity, CCF0054500 lowered platelet reactivity (P<0.0001) and improved left ventricular function (P=0.0007). CONCLUSIONS: We describe and characterize the first nonolfactory probe for the purpose of inhibiting platelet activation and thrombosis through downstream HSP27 in a comprehensive investigation using a first-of-its-kind platelet inhibitor targeting an orphan platelet GPCR.
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Aggarwal et al. (2026) studied Coronary artery and peripheral artery disease. CCF0054500 was evaluated on Clot retraction (clot area) (p=<0.0001). The OR2L13 agonist CCF0054500 reduced clot retraction area (5.2 vs 70.6; P<0.0001) and decreased platelet accumulation by 88.9% (P<0.0003) in a murine arterial injury model.
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