Pepducin

Pepducins are novel 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 utilize lipidated fragments of intracellular G protein-coupled receptor loops to modulate GPCR action in targeted cell-signaling pathways.^[2] A pepducin molecule comprises 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] and progress continues to be made.^[6][7]

References

1. Covic L, Gresser AL, Talavera J, Swift S, Kuliopulos A (January 2002). "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. doi:10.1073/pnas.022460899. PMC 117359. PMID 11805322.
2. Kuliopulos A, Covic L (December 2003). "Blocking receptors on the inside: pepducin-based intervention of PAR signaling and thrombosis". Life Sci. 74 (2–3): 255–62. doi:10.1016/j.lfs.2003.09.012. PMID 14607253.
3. Kubo S, Ishiki T, Doe I, et al. (December 2006). "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. doi:10.1196/annals.1378.087. PMID 17341635.
4. "Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.". 2010.
5. Zhang, P., Gruber, A., Kasuda, S., Kimmelstiel, C., O’Callaghan, K., Bohm, A., Baleja, J.D., Covic, L., & Kuliopulos, A. (2012). "Suppression of Arterial Thrombosis with Affecting Hemostatic Parameters with a Cell-Penetrating PAR1 Pepducin". Circulation 126: 83–91. doi:10.1161/circulationaha.112.091918. PMID 22705889.
6. Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A (2011). "Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models". Methods in Molecular Biology. Methods in Molecular Biology (Clifton, N.J.) 683: 259–75. doi:10.1007/978-1-60761-919-2_19. ISBN 978-1-60761-918-5. PMID 21053136.
7. 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: 12787–96. doi:10.1074/jbc.r112.355461. PMID 22374997.