Chemistry:Pepducin
Pepducins are cell-penetrating peptides that act as intracellular modulators of signal transference from receptors to G proteins. Pepducins were first developed at the Tufts Medical Center laboratories of Dr. Athan Kuliopulos and Dr. Lidija Covic.[1] Pepducins employ lipidated fragments of intracellular G protein-coupled receptor loops to modulate GPCR action in targeted cell-signaling pathways.[2] A pepducin molecule consists of a short peptide derived from a GPCR intracellular loop tethered to a hydrophobic moiety. This structure allows pepducin lipopeptides to anchor in the cell membrane lipid bilayer and target the GPCR/G protein interface via a unique intracellular allosteric mechanism. Pepducins for over 15 different GPCRs have been successfully produced, several of which have shown activity in preclinical in vivo models.[3]
An anti-PAR4 pepducin extended bleeding time in mice and protected against systemic platelet activation and thrombosis.[2]
A CXCR4 agonist pepducin mobilizes bone marrow hematopoietic cells.[4]
A PAR1 pepducin, PZ-128, has successfully completed phase I clinical trials.[5][6][7]
References
- ↑ "Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 643–8. January 2002. doi:10.1073/pnas.022460899. PMID 11805322. Bibcode: 2002PNAS...99..643C.
- ↑ 2.0 2.1 "Blocking receptors on the inside: pepducin-based intervention of PAR signaling and thrombosis". Life Sci. 74 (2–3): 255–62. December 2003. doi:10.1016/j.lfs.2003.09.012. PMID 14607253.
- ↑ "Distinct activity of peptide mimetic intracellular ligands (pepducins) for proteinase-activated receptor-1 in multiple cells/tissues". Ann. N. Y. Acad. Sci. 1091: 445–59. December 2006. doi:10.1196/annals.1378.087. PMID 17341635.
- ↑ "Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.". 2010. http://bonegrafts.researchtoday.net/archive/7/12/9158.htm.
- ↑ Zhang, P.; Gruber, A.; Kasuda, S.; Kimmelstiel, C.; O’Callaghan, K.; Bohm, A.; Baleja, J.D.; Covic, L. et al. (2012). "Suppression of Arterial Thrombosis with Affecting Hemostatic Parameters with a Cell-Penetrating PAR1 Pepducin". Circulation 126 (1): 83–91. doi:10.1161/circulationaha.112.091918. PMID 22705889.
- ↑ "Pharmacology, Biodistribution, and Efficacy of GPCR-Based Pepducins in Disease Models". Cell-Penetrating Peptides. Methods in Molecular Biology. 683. Clifton, N.J.. 2011. pp. 259–75. doi:10.1007/978-1-60761-919-2_19. ISBN 978-1-60761-918-5.
- ↑ O’Callaghan, K.; Kuliopulos, A.; Covic, L. (2012). "Turning Receptors On and Off with Intracellular Pepducins: New Insights into G-protein Coupled Receptor Drug Development". J Biol Chem 287 (16): 12787–96. doi:10.1074/jbc.r112.355461. PMID 22374997.
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