Conformational analyses of somatostatin-related cyclic hexapeptides containing peptoid residues.
We report the conformational analysis by 1H NMR in DMSO and computer simulations involving distance geometry and molecular dynamics simulations of a series of peptoid analogues of the cyclic hexapeptide c[Phe11-Pro6-Phe7-d-Trp8-Lys9-Thr10] (1). The proline residue in compound 1 is replaced with the peptoid residues N-benzylglycine (Nphe) (compound 2), N-(S)-alpha-methylbenzylglycine [(S)-beta-MeNphe] (compound 3), and N-(R)-alpha-methylbenzylglycine [(R)-beta-MeNphe] (compound 4). The peptoid analogues 2 and 4 exhibit potent binding activities to the hsst2 receptor, while the binding affinities to the hsst5 and to the hsst3 receptors are reduced compared to that of the parent compound 1. Compound 3 shows reduced binding activities to the hsst2, hsst3, and hsst5 receptors compared to compound 1. The results of in vivo assays indicate that these compounds inhibit the growth hormone release but do not affect the insulin release. These peptoid-containing analogues show two sets of NMR signals corresponding to cis and trans conformations of the peptide bond between Phe11 and Nxaa6. We demonstrate that the backbone conformation and the orientation of the relevant side chains of compound 1 are maintained in the cis isomers of the peptoid analogues which adopt a type VI beta-turn centered around residues 11 and 6 and a type II' beta-turn with d-Trp in the i+1 position. The enhanced selectivity of the peptoid-containing analogues compared to compound 1 and the results of the conformational analysis suggest that the presence of a conformationally constrained hydrophobic group in position 6 in complementary topology to the Phe11 side chain enhances selective binding to the hsst2 receptor.
Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0343, USA.
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D003198:Computer Simulation; D004121:Dimethyl Sulfoxide; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D034444:Peptoids; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D010446:Peptide Fragments; D034444:Peptoids; D017481:Receptors, Somatostatin; C113342:cyclo(N-benzylglycyl-phenylalanyl-tryptophyl-lysyl-threonyl-phenylalanyl); C040704:cyclo(Pro-Phe-Trp-Lys-Thr-Phe); C113341:cyclo(beta-methyl-N-benzylglycyl-phenylalanyl-tryptophyl-lysyl-threonyl-phenylalanyl); C103631:somatostatin receptor 3; D013004:Somatostatin; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; D004121:Dimethyl Sulfoxide