The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

Nonpeptide Angiotensin II Receptor Antagonists: The Next Generation in Antihypertensive Therapy

Classification of scaffold-hopping approaches.

The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of native peptides. They can be either combined with α-amino acids by following specific patterns, which results in backbone architectures with well-defined orientations of the side chain functional groups, or assembled in de novo-designed bioactive β- or α,β-peptidic sequences. Such peptides display various biological functions, including antimicrobial activity, inhibition of protein–protein interactions, agonism/antagonism of GPCR ligands, and anti-angiogenic activity.

http://pubs.acs.org/doi/pdf/10.1021/jm5010896

Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry.

G protein-coupled receptors (GPCRs) constitute the largest family of cellular receptors involved in signal transduction. A review is given of the voluminous structural and/or activity evidence in support of a ligand turn shape being the likely recognition domain in GPCR-binding domains of all of these ligands. In the absence of structurally defined GPCR-ligand complexes, solution or solid-state structures are analyzed for a variety of GPCR-binding ligands alone, including (i) peptide and protein hormone ligands, (ii) bioactive peptide fragments, (iii) cyclic peptides, often analogous of protein segments, (iv) peptidomimetic antagonists with a conformational bias enforced by the presence of turn-inducing constraints. Examples of small cyclic peptidomimetics for naturally occurring GPCR-binding small peptides are also covered, including, somatosatin (14 residues), melanocyte-stimulating hormone (13), oxytocin (9), vasopressin (9), substance P (11), bradykinin (9), opiod peptides, and small fragments of proteins.

Over one hundred peptide-activated G protein-coupled receptors recognize ligands with turn structure.

Conformations of two cyclic analogs of angiotensin (Asp1-Arg2-Val3-Tyr4-Val/Ile5-His6-Pro7-Phe8, AT), cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, were studied, independently employing two complementary techniques, energy calculations and NMR measurements in DMSO solution. NMR data were indicative of well-defined solution conformations for the cyclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT, including the phi values for the Cys3/HCys3 and Tyr4 residues, as well as the chi 1 value for the Tyr4 residue. Solution conformations for the exocyclic linear parts of both molecules cannot be described by the NMR data with the same precision. At the same time, independent energy calculations revealed the same conformations of cyclic moieties of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT among low-energy conformers for both peptides. Moreover, the same conformations are compatible with the model of AT receptor-bound conformation (Nikiforovich & Marshall, 1993), which assumes the particular spatial arrangement of aromatic moieties of Tyr4, His6, and Phe8 residues and the C-terminal carboxyl. These conformers of cyclo[Sar1, Cys3, Mpt5]-AT and cyclo[Sar1, HCys3, Mpt5]-AT contain "an open turn" in the backbone of the Tyr4-Val5 residues, instead of the earlier proposed beta-like reversal, thus confirming the suggestion that the conformation(s) ensuring binding of AT analogs with specific receptors should not be described in terms of a unique backbone conformer.

Conformational analysis of two cyclic analogs of angiotensin: implications for the biologically active conformation.

The β-turn is a well-studied motif in both proteins and peptides. Four residues, making almost a complete 180°-turn in the direction of the peptide chain, define the β-turn. Several types of the β-turn are defined according to Φ and Ψ torsional angles of the backbone for residues i + 1 and i + 2. One special type of β-turn, the type VI-turn, usually contains a proline with a cis-amide bond at residue i + 2. In an aza-amino acid, the α-carbon of the amino acid is changed to nitrogen. Peptides containing azaproline (azPro) have been shown to prefer the type VI β-turn both in crystals and in organic solvents by NMR studies. MC/MD simulations using the GB/SA solvation model for water explored the conformational preferences of azPro-containing peptides in aqueous systems. An increase in the conformational preference for the cis-amide conformer of azPro was clearly seen, but the increased stability was relatively minor with respect to the trans-conformer as compared to previous suggestions. To test the validity...

Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues.

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.

http://link.springer.com/content/pdf/10.1007/978-94-011-1474-5_139.pdf

Wei-Jun Zhang

Papers

Conformational analysis of two cyclic analogs of angiotensin: implications for the biologically active conformation.

Impact of azaproline on amide cis-trans isomerism: conformational analyses and NMR studies of model peptides including TRH analogues.

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

Chimeric amino acids as tools in conformational analysis: Bradykinin and angiotensin II

Synthesis of gramicidin analogs with conformationally constrained dipeptides