P4pal10 (trifluoroacetate salt) (Synonyms: Palmitoyl-SGRRYGHALR-amide, Palmitoyl-SGRRYGHALR-NH2)

P4pal10 is a pepducin antagonist of proteinase-activated receptor 4 (PAR4) and formyl peptide receptor 2 (FPR2), as well as an agonist of free fatty acid receptor 2 (FFAR2/GPR43).^1,2 It is composed of a peptide that corresponds to the third intracellular loop of human PAR4 that is conjugated to palmitic acid .¹ P4pal10 selectively inhibits the aggregation of isolated human platelets induced by the PAR4 peptide agonist AYPGKF-NH₂ over the PAR1 peptide agonist SFLLRN-NH₂ , the TP receptor agonist U-46619 , the platelet glycoprotein Ib (GPIb), GPIX, and GPV agonist ristocetin, ADP , or collagen at 5 µM. It inhibits increases in intracellular calcium induced by the FPR1 and FPR2 agonist WKYMVm but not by the FPR1 agonist fMLF in isolated human neutrophils and induces superoxide production in TNF-α primed isolated human neutrophils stimulated with the FFAR2 allosteric modulator Cmp58.² P4pal10 (1, 3, or 10 µg/kg) reduces myocardial infarct size in a rat model of coronary artery ligation-induced ischemia-reperfusion injury.³ It increases the paw withdrawal threshold in rat models of osteoarthritis induced by monoiodoacetate injection into the knee joint or medial meniscal transection.⁴

1.Covic, L., Misra, M., Badar, J., et al.Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activationNat. Med.8(10)1161-1165(2002) 2.Holdfeldt, A., Lind, S., Hesse, C., et al.The PAR4-derived pepducin P4Pal10 lacks effect on neutrophil GPCRs that couple to Gαq for signaling but distinctly modulates function of the Gαi-coupled FPR2 and FFAR2Biochem Pharmacol.114143(2020) 3.Strande, J.L., Hsu, A., Su, J., et al.Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signalingJ. Pharmacol. Exp. Ther.324(3)1045-1054(2008) 4.O'Brien, M.S., and McDougall, J.J.Targeting proteinase activated receptor-4 reduces mechanonociception during the acute inflammatory phase but not the chronic neuropathic phase of osteoarthritis in ratsFront. Pharmacol.12756632(2021)