Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor(421 views) De Luca S, Saviano M, Della Moglie R, Digilio G, Bracco C, Aloj L, Tarallo L, Pedone C, Morelli G
Keywords: Cholecystokinin, Cyclic Constraints, Nmr Structures, Peptides, Receptors, Cholecystokinin Receptor, Drug Derivative, Ligand, Peptide Library, Article, Chemical Structure, Chemistry, Conformation, Drug Antagonism, Drug Design, Nuclear Magnetic Resonance Spectroscopy, Synthesis, Models, Molecular, Molecular Conformation,
Affiliations: *** IBB - CNR ***
Istituto di Biostrutture e Bioimmagini-CNR, Centro Interuniversitario per la Ricerca Sui Peptidi Bioattivi (CIRPeB), Via Mezzocannone 16, 80134 Napoli, Italy
Bioindustry Park del Canadese, Via Ribes 5, 10010 Colleretto Giocosa, Italy
Department of Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G. Pascale, Via M. Semmola, 80131 Napoli, Italy
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Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor
A library of 14 cyclic peptide analogues derived from the octapeptide C-terminal sequence of the human cholecystokinin hormone (CCK (26-33), or CCK8) was designed, synthesized, and characterized. The 14 peptide analogues were rationally designed to specifically interact with the CCK type B receptor (CCK8-R) on the basis of the structure of the bimolecular complex between CCK8 and the third extracellular loop of CCK8-R, namely CCK8-R- (352-379). The rational design of new ligands for CCK 8-R has relied on stabilization by cyclic constraints of the structural motifs that bring the key residues of the ligand (especially Trp 30, Met31, and Phe33) in the proper spatial orientation for optimal interaction with the receptor. The binding affinity of the new ligands for CCK8-R was assessed by displacement experiments of 111In-radiolabeled CCK8 in cells that overexpress the CCK8 receptor. The new ligands generally showed binding affinities lower than that of parent CCK8, with the best compounds having IC50 values around 10 M. Structure-activity relationship data show that preservation of the Trp30-Met31 motif is essential and that the Phe33 side chain must be present. NMR conformational studies of the compound with maximal binding affinity (cyclo-B11, IC50 = 11 M) in DPC micelles shows that this compound presents a turn-like conformation centered at the Trp 30-Met31 segment, as planned by rational design. Such a conformation is stabilized by its interaction with the micelle rather than by the cyclic constraint. 2006 Wiley-VCH Verlag GmbH & Co. KGaA
Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor
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Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor
Aloj L, Aurilio M, Rinaldi V, D'Ambrosio L, Tesauro D, Peitl PK, Maina T, Mansi R, Von Guggenberg E, Joosten L, Sosabowski JK, Breeman WA, De Blois E, Koelewijn S, Melis M, Waser B, Beetschen K, Reubi JC, De Jong M * The EEE project(449 views) Proc Int Cosm Ray Conf Icrc Universidad Nacional Autonoma De Mexico, 2007; 5(HEPART2): 977-980. Impact Factor:0 ViewExport to BibTeXExport to EndNote