Cyclic pentapeptides of chiral sequence DLDDL 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

Abstract

Under the hypotheses of a structurally related binding site for antagonists of G-protein coupled receptors and the ability of cyclic pentapeptides of chiral sequence D1L2D3D4L5 to form rigid structures with which probe the pharmacophoric specificity of these receptors, inhibitors of substance P were designed based on available structure-activity relationships. ITF 1565, cyclo[D-Trp1-Pro2-D-Lys3-D-Trp4-Phe5], antagonized substance P activity mediated by type 1 neurokinin receptor (NK1) whereas it acted weakly against NK2 and did not inhibit endothelin at all. The preferential conformation of the peptide was obtained from nmr spectroscopy and computer calculations, and shown to contain the same beta II-turn and gamma'-turn found in other cyclic pentapeptides with the same chiral sequence. The structure of the peptide was compared with that of the beta-D-glucose molecule that has been proposed as a semirigid scaffold for antagonists of G-protein coupled receptors. The gamma'-turn of the cyclic peptide superimposed well with beta-D-glucose in the chair conformation. Furthermore, when the side chains were considered, the aromatic groups of the two molecules were found to generally overlap. These results support the view of G-protein coupled receptors as possessing structurally similar binding sites for antagonists and suggest that cyclic pentapeptides of chiral sequence D1L2D3D4L5 may be useful as semirigid scaffolds for the design of antagonists of this family of receptors.

Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar αVβ3/αVβ5Integrin Dual Binders

“…Biological Results. The ability of cyclopeptides 1 − 11 to compete with [ 125 I]-echistatin for binding to the isolated, purified α V β 3 and α V β 5 receptors was evaluated in a solid-phase receptor assay 17 and compared with that of known standard binders, EMD121974,14a c(-RGDfV-),2b and ST1646 3b. Integrin-coated 96-well plates were incubated with the ligand in the presence of serially diluted competing compounds.…”

“…In the recent past, small molecular templates that mimic or induce loop and turn secondary structural features of peptides and proteins have gained ample popularity due to the important role they play in molecular recognition and biological events . In particular, great effort is focused on the design and synthesis of a number of molecular platforms encompassing dipeptide core structures, constrained dipeptide surrogates, and nonpeptide motifs, whose incorporation into known peptide sequences has resulted in the creation of promising cyclic and acyclic entities targeting diverse, therapeutically relevant receptors and enzymes. Among the most sought after receptors, the integrin family represents an enterprising biological target, for their diverse components play a prime role in physiopathological processes that span from coagulation of blood, tumor-induced angiogenesis, and control of the immune system to the initiation and progression of tumor metastasis, osteoporosis, restenosis, and inflammatory diseases …”

“…In the present work, we focused on α V β 3 and α V β 5 integrin receptors, which recognize several matrix proteins through the Arg-Gly-Asp (RGD) tripeptide sequence. , Today, several major classes and compounds are presented as effective binders of α V β 3 and α V β 5 , where proper inducers of secondary peptide structure are grafted onto the RGD sequence to prevent free rotation of the amide linkages and project peripheral substituents in proper spatial orientations. 2b,3b,7e, …”

Development of Anti-HIV Agents Targeting Dynamic Supramolecular Mechanism: Entry and Fusion Inhibitors Based on CXCR4/CCR5 Antagonists and gp41-C34-Remodeling Peptides

“…Thus, the pharmacophore-guided approach based on these four residues might lead to the development of low molecular weight CXCR4 antagonists. Cyclic pentapeptides have been utilized as conformationally restricted templates disposing functional groups in medicinal chemistry [28,31,32,61,73,98], e.g. in efficient discovery of bioactive lead compounds such as integrin antagonists [31,32,98] and endothelin antagonists [28,73].…”

Peptide interactions with G-protein coupled receptors

“…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.…”