PAR4 (1-6) (human)
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PAR4 (1-6) (human)

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PAR4 (1-6) is a synthetic hexapeptide agonist of proteinase-activated receptor 4 (PAR4). PAR4 is a thrombin receptor activated by platelet, and acts as a modulator of cellular responses that serve as hallmarks of inflammation.

Category
Peptide Inhibitors
Catalog number
BAT-006098
CAS number
225779-44-2
Molecular Formula
C28H41N7O9
Molecular Weight
619.67
PAR4 (1-6) (human)
Size Price Stock Quantity
25 mg $298 In stock
IUPAC Name
(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-1-[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-methylbutanoic acid
Synonyms
H-Gly-Tyr-Pro-Gly-Gln-Val-OH; (2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-1-[(2S)-2-[(2-aminoacetyl)amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-3-methylbutanoic acid
Appearance
Crystalline Solid
Purity
98%
Sequence
GYPGQV
InChI
InChI=1S/C28H41N7O9/c1-15(2)24(28(43)44)34-25(40)18(9-10-21(30)37)32-23(39)14-31-26(41)20-4-3-11-35(20)27(42)19(33-22(38)13-29)12-16-5-7-17(36)8-6-16/h5-8,15,18-20,24,36H,3-4,9-14,29H2,1-2H3,(H2,30,37)(H,31,41)(H,32,39)(H,33,38)(H,34,40)(H,43,44)/t18-,19-,20-,24-/m0/s1
InChI Key
VTCFYKYDKDAJKZ-XHOYROJHSA-N
Canonical SMILES
CC(C)C(C(=O)O)NC(=O)C(CCC(=O)N)NC(=O)CNC(=O)C1CCCN1C(=O)C(CC2=CC=C(C=C2)O)NC(=O)CN
1. Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCdelta in platelets
Robert T Dorsam, Satya P Kunapuli, Jianguo Jin, Haripriya Shankar, Swaminathan Murugappan, Surya Bhamidipati Blood . 2005 Jul 15;106(2):550-7. doi: 10.1182/blood-2004-12-4866.
Thrombin has been known to cause tyrosine phosphorylation of protein kinase C delta (PKCdelta) in platelets, but the molecular mechanisms and function of this tyrosine phosphorylation is not known. In this study, we investigated the signaling pathways used by protease-activated receptors (PARs) to cause tyrosine phosphorylation of PKCdelta and the role of this event in platelet function. PKCdelta was tyrosine phosphorylated by either PAR1 or PAR4 in a concentration- and time-dependent manner in human platelets. In particular, the tyrosine 311 residue was phosphorylated downstream of PAR receptors. Also the tyrosine phosphorylation of PKCdelta did not occur in Galpha(q)-deficient mouse platelets and was inhibited in the presence of a phospholipase C (PLC) inhibitor U73122 and calcium chelator BAPTA (5,5'-dimethyl-bis(o-aminophenoxy)ethane-N, N, N ', N '-tetraacetic acid), suggesting a role for Galpha(q) pathways and calcium in this event. Both PAR1 and PAR4 caused a time-dependent activation of Src (pp60c-src) tyrosine kinase and Src tyrosine kinase inhibitors completely blocked the tyrosine phosphorylation of PKCdelta. Inhibition of tyrosine phosphorylation or the kinase activity of PKCdelta dramatically blocked PAR-mediated thromboxane A2 generation. We conclude that thrombin causes tyrosine phosphorylation of PKCdelta in a calcium- and Src-family kinase-dependent manner in platelets, with functional implications in thromboxane A2 generation.
2. Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets
Summer Young, Jonathan Schoenecker, Matthew Duvernay, Heidi E Hamm, David Gailani Mol Pharmacol . 2013 Apr;83(4):781-92. doi: 10.1124/mol.112.083477.
With the recent interest of protease-activated receptors (PAR) 1 and PAR4 as possible targets for the treatment of thrombotic disorders, we compared the efficacy of protease-activated receptor (PAR)1 and PAR4 in the generation of procoagulant phenotypes on platelet membranes. PAR4-activating peptide (AP)-stimulated platelets promoted thrombin generation in plasma up to 5 minutes earlier than PAR1-AP-stimulated platelets. PAR4-AP-mediated factor V (FV) association with the platelet surface was 1.6-fold greater than for PAR1-AP. Moreover, PAR4 stimulation resulted in a 3-fold greater release of microparticles, compared with PAR1 stimulation. More robust FV secretion and microparticle generation with PAR4-AP was attributable to stronger and more sustained phosphorylation of myosin light chain at serine 19 and threonine 18. Inhibition of Rho-kinase reduced PAR4-AP-mediated FV secretion and microparticle generation to PAR1-AP-mediated levels. Thrombin generation assays measuring prothrombinase complex activity demonstrated 1.5-fold higher peak thrombin levels on PAR4-AP-stimulated platelets, compared with PAR1-AP-stimulated platelets. Rho-kinase inhibition reduced PAR4-AP-mediated peak thrombin generation by 25% but had no significant effect on PAR1-AP-mediated thrombin generation. In conclusion, stimulation of PAR4 on platelets leads to faster and more robust thrombin generation, compared with PAR1 stimulation. The greater procoagulant potential is related to more efficient FV release from intracellular stores and microparticle production driven by stronger and more sustained myosin light chain phosphorylation. These data have implications about the role of PAR4 during hemostasis and are clinically relevant in light of recent efforts to develop PAR antagonists to treat thrombotic disorders.
3. Dabigatran enhances platelet reactivity and platelet thrombin receptor expression in patients with atrial fibrillation
A Achilles, A Mohring, M Kelm, B Levkau, J W Fischer, T Hohlfeld, T Zeus, M Grandoch, A Polzin, L Dannenberg J Thromb Haemost . 2017 Mar;15(3):473-476. doi: 10.1111/jth.13595.
Essentials Whether or not dabigatran enhances the risk of myocardial infarction is under discussion. We measured platelet reactivity and thrombin receptor expression in dabigatran patients. Platelet reactivity and thrombin receptor expression is enhanced during dabigatran treatment. This should be considered when choosing the optimal direct oral anticoagulant for individuals.Summary:Background The direct oral anticoagulant (DOAC) dabigatran is a direct thrombin inhibitor. Its landmark trial, the RE-LY study, observed a trend towards a higher incidence of myocardial infarctions (MIs) in dabigatran-treated patients. Since then, there have been discussions on whether dabigatran increases the risk of MI. Objective In this study, we aimed to assess platelet reactivity and platelet thrombin receptor expression in dabigatran-treated patients. Methods We conducted a cross-sectional study in 13 hospitalized patients with planned initiation of dabigatran medication. Platelet reactivity was measured by light-transmission aggregometry and platelet thrombin receptor expression was measured by flow cytometry analysis. Results Platelet reactivity was higher after initiation of dabigatran medication as compared with baseline (baseline 44 ± 24% vs. dabigatran 70 ± 25%). Accordingly, the density of both platelet thrombin receptors (protease activated receptor [PAR]-1 and PAR-4) on platelets increased during dabigatran treatment (PAR1, baseline 63 ± 11% vs. dabigatran 70 ± 10%; PAR4, baseline 1.1 ± 0.5% vs. dabigatran 1.6 ± 0.9%). Conclusions Dabigatran increases platelet reactivity by enhancing the thrombin receptor density on platelets. This finding should be considered while choosing the optimal DOAC in individualized medicine.
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