Pepducin
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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]
As of 2011 none have entered clinical trials,[5] although progress continues to be made.[6][7]
References
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=117359.
- ^ a b 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. http://linkinghub.elsevier.com/retrieve/pii/S0024320503008312.
- ^ 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.
- ^ "Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells.". 2010. http://bonegrafts.researchtoday.net/archive/7/12/9158.htm.
- ^ Dimond (4 Oct 2010). "Innovations in Peptide Structure Pushing Candidates through Development". http://www.genengnews.com/keywordsandtools/print/3/20663/.
- ^ 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 (Clifton, N.J.). Methods in Molecular Biology 683: 259–75. doi:10.1007/978-1-60761-919-2_19. ISBN 978-1-60761-918-5. PMID 21053136.
- ^ Dimond P, Carlson K, Bouvier M, Gerard C, Xu L, Covic L, Agarwal A, Ernst OP, Janz JM, Schwartz TW, Gardella TJ, Milligan G, Kuliopulos A, Sakmar TP, Hunt SW (May 2011). "G protein-coupled receptor modulation with pepducins: moving closer to the clinic". Annals of the New York Academy of Sciences 1226: 34–49. doi:10.1111/j.1749-6632.2011.06039.x. PMID 21615752.
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