Cyclic pentapeptides of chiral sequenceDLDDL as scaffold for antagonism of G-protein coupled receptors: Synthesis, activity and conformational analysis by NMR and molecular dynamics of ITF 1565 a substance P inhibitor

Porcelli, Massimiliano; Casu, Mariano; Laı̈, Adolfo; Saba, Giuseppe; Pinori, Massimo; Cappelletti, Silvana; Mascagni, Paolo

doi:10.1002/(sici)1097-0282(199908)50:2<211::aid-bip10>3.0.co;2-e

Cited by 16 publications

(1 citation statement)

References 31 publications

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“…32,91 Porcelli et al utilized this approach to discover a novel substance P antagonist. 92 Haskell-Luevano et al screened a library of 951 compounds based upon the ␤-turn motif and identified the first two nonpeptidic heterocyclic micromolar agonists associated with the melanocortin-1 receptor. 93 Another example is the rapid identification of selective agonists of the five somatostatin-receptor subtypes through combinatorial chemistry, important pharmacological tools for understanding their physiological roles in therapeutics.…”

Section: Combinatorial Chemistrymentioning

confidence: 99%

Peptide interactions with G-protein coupled receptors

Marshall

2001

Biopolymers

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Peptide recognition by G-protein coupled receptors (GPCRs) is reviewed with an emphasis on the indirect approach used to determine the receptor-bound conformation of peptide ligands. This approach was developed in response to the lack of detailed structural information available for these receptors. Recent advances in the structural determination of rhodopsin (the GPCR of the visual system) by crystallography have provided a scaffold for homology modeling of the inactive state of a wide variety of GPCRs that interact with peptide messages. Additionally, the ability to mutate GPCRs and assay compounds of similar chemical structure to test a common binding site on the receptor provides a firm experimental basis for structure-activity studies. Recognition motifs, common in other well-studied systems such as proteolytic enzymes and major histocompatibility class receptors (MHC) are reviewed briefly to provide a basis of comparison. Finally, the development of true peptidomimetics is contrasted with nonpeptide ligands, discovered through combinatorial chemistry. In many systems, the evidence suggests that the peptide ligands bind at the interface between the transmembrane segments and the extracellular loops, while nonpeptide antagonists bind within the transmembrane segments. Plausible models of GPCRs and the mechanism by which they activate G-proteins on binding peptides are beginning to emerge.

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Section: Combinatorial Chemistrymentioning

confidence: 99%

Peptide interactions with G-protein coupled receptors

Marshall

2001

Biopolymers

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Synthesis of Aib‐ and Phe(2Me)‐Containing Cyclopentapeptides

Arnhold

Linden

Heimgartner

2015

Helvetica Chimica Acta

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Some recently described pentapeptides containing the alpha,alpha-disubstituted alpha-amino acids Aib and Phe(2Me) have been cyclized in DMF solution using diphenyl phosphorazidate (DPPA), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetamethyluronium tetrafluoroborate/1-hydroxybenzotriazole (TBTU/HOBt), and diethyl phosphorocyanidate (DEPC), respectively, to give the corresponding cyclopentapeptides in fair-to-good yields. In the case of peptides with L-amino acids, and (R)-and (S)-Phe(2Me), the yields differed significantly in favor of the L/(R) combination. The conformations in the crystals of cyclo(GlyAib-(R,S)-Phe(2Me)-Aib-Gly) and cyclo(Gly-(R)-Phe(2Me)-Pro-Aib-Gly) have been determined by Xray crystallography, leading to quite different results. In the latter case, the conformation in solution has been elucidated by NMR studies.

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