Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.

Vinyl sulfide cyclized analogues of angiotensin II with high affinity and full agonist activity at the AT(1) receptor.

Therapeutic peptides and peptidomimetics.

The most prevalent physiological effects of ANG II, the main product of the renin-angiotensin system, are mediated by the AT1 receptor, a rhodopsin-like AGPCR. Numerous studies of the cardiovascula...

https://www.physiology.org/doi/pdf/10.1152/physrev.00040.2005

The Angiotensin II AT1 Receptor Structure-Activity Correlations in the Light of Rhodopsin Structure

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.

Peptide interactions with G‐protein coupled receptors

Macrocyclic peptides and peptide-containing molecules are attractive molecular scaffolds for the development of bioactive compounds to modulate biomolecular interactions. These structures combine a high degree of functional complexity with restricted conformational flexibility, which make them well-suited to achieve selective and tight binding to extended biomolecular interfaces, such as those mediating protein– protein and protein–nucleic acid complex formation. Compared to linear peptides, conformationally constrained peptide-based ligands often exhibit higher proteolytic stability, enhanced cell permeability, and higher affinity towards the target biomolecule, which render them valuable as probes and potential pharmacological agents. Indeed, many cyclic and lariat peptides isolated from natural sources exhibit potent biological activities and have provided a source of viable drugs. Both biosynthetic and synthetic methods have been implemented to afford peptides in cyclic or conformationally constrained configurations. Genetic encoding offers the unrivalled advantage that vast molecular libraries (10–10) can be rapidly created by combinatorial mutagenesis and readily explored using genetic selection or ultrahigh-throughput screening methods. However, the pool of building blocks available for construction of biological peptide libraries remains restricted, limiting the degree of ligand diversity achievable through these approaches. In contrast, synthetic methods can draw upon a much broader spectrum of precursor structures, including non-natural amino acids, peptoids, and amino acid unrelated scaffolds, which can be exploited to confer improved or novel conformational and target-binding properties to peptide-based ligands. Integrating the advantages of biological and synthetic approaches would open unprecedented opportunities for ligand diversification and molecular discovery. Towards this goal, we have developed a method that allows the embedding of non-proteogenic synthetic moieties into genetically encoded peptidic frameworks. This strategy enables the modular assembly of macrocyclic organo–peptide hybrids (MOrPHs), the size and composition of which can be readily diversified by varying the nature of the synthetic and biosynthetic precursors (Scheme 1). Our approach takes advantage of the reactivity of intein proteins and the opportunity to introduce bioorthogonal functionalities into proteins by amber stop codon suppression. We envisioned that incorporating an alkyne-bearing non-natural amino acid within the N-terminal portion of an intein-fused polypeptide would yield a recombinant protein carrying two functional groups with orthogonal reactivity, namely the alkyne moiety and the thioester bond transiently formed at the junction with the intein by reversible N!S acyl transfer. A tandem chemoselective reaction could thus be exploited to mediate coupling of this biosynthetic precursor (BP) to an azide/hydrazide-containing synthetic precursor (SP) and promote the formation of an organo–peptide macrocycle (Scheme 1). To test our design, we first constructed a plasmid (pBP_MG6) encoding for a 6mer target sequence (TS6: TGSYGT) preceded by Met, Gly, and the amber stop codon TAG and fused at the C terminus to the N-terminal cysteine of intein GyrA from Mycobacterium xenopi. This construct was expressed in E. coli in the presence of O-propargyltyrosine (OpgY) and a previously described mutant tRNACUA (MjtRNACUA)/tyrosyl-tRNA synthetase (MjTyrRS) pair [15]

Modular Assembly of Macrocyclic Organo–Peptide Hybrids Using Synthetic and Genetically Encoded Precursors

To study the conformational features of molecular recognition of angiotensin II (Asp1-Arg2-Val3-Tyr4-Val/Ile5-His6-Pro7-Phe8, AII), the synthesis and biological testing of several cyclic analogs of AII cyclized between positions 5 and 7 have been performed. The synthesized analogs were Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Pen7)-Phe8 (3), Sar1-Arg2-Val3-Tyr4-cyclo(Asp5-His6-Apt7)-Phe8 (4), Sar1-Arg2-Val3-Tyr4-cyclo(Glu5-His6-Apt7)-Phe8 (5), Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpt7)-Phe8 (6), Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpc7)-Phe8 (7), Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpt7)-Phe8 (8), and Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpc7)-Phe8 (9), where Apt stands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto-trans- and -cis-prolines, respectively. Compound (9) showed good affinity at AT-1 receptors, namely a KD = 20 nM. In functional assays, it showed the characteristics of a weak partial agonist with a relative affinity of 0.26% of that for AII and an intrinsic efficacy, αE, of 0.42. Molecula...

Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications.

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Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications.