Multiple binding modes for the receptor-bound conformations of cyclic AII agonists

Abstract

Angiotensin II, Asp-Arg-Val-Tyr-His-Pro-Phe, binds its receptor with a postulated turn centered at residue four. Analogs of angiotensin II which contain a disulfide bridge between the side chains of residues 3 and 5 retain significant activity consistent with this hypothesis. Incorporation of 4-mercaptoproline residues, a hybrid, or chimeric amino acid which combines the properties of proline and homocysteine, into either of these positions with analogous disulfide bridges allows retention of high affinity for the receptor. These more highly constrained bicyclic systems give new insight into the details of molecular recognition of residues 3-5 of angiotensin by the receptor. Retention of activity by the antiparallel dimer of [Sar1,Cys3,5]-AII in which the peptide backbone is held in an extended conformation was unexpected. Analysis of the conformational constraints imposed in these active analogs suggests that AII agonists bind to their receptor with different backbone conformations in the region of the central tyrosine residue.

Impact of Cis‐proline analogs on peptide conformation

“…As compared to most other types of VI-turn mimetics, azaproline not only strongly stabilizes the cis-amide bond, but also constrains backbone torsions to those associated with structures that satisfy the type VIturn conformation, and does not introduce additional steric bulk that could compromise receptor interactions. The availability of hybrid or chimeric proline analogs, [87][88][89][90][91][92][93][94][95] where side-chain functional groups have been attached to the pyrrolidine ring suggests that the preparation of similar chimeric proline analogs with both diverse side-chain functionality and constrained backbone conformations would give novel receptor probes as type VI -turns and sheds new insight on the details of receptor recognition.…”

Conformational analysis of cyclic angiotensin II analogues

“…The analogues selected for conformational analysis were c[Sarl,Lys3,GluS]ANG II (15% activity of ANG II in rat uterus assay [8]) and c[Sar ~, Hcy3,MptS]ANG II (binding affinity to rat liver nearly the same as that of ANG II [5] Conformational analysis was performed, using ECEPP potential functions and standard geometry [9,10] with rigid bond lengths and valence angles. The Arg 2 side chain and the N-and C-terminal groups were treated in charged forms.…”

“…One of the aims of these studies was to determine a receptor-bound ('biologically active') conformation of ANG II. Different models of biologically active conformations of ANG II were proposed [2][3][4][5][6][7]. Most of them are compact structures folded in the central part of the molecule.…”

“…The synthesis of cyclic ANG II analogues by linking residues at positions 3 and 5 gave series of active analogues [5,8]. Cyclisation considerably reduces the conformational mobility of ANG II, and we tested whether it was possible to develop a model of receptor-bound conformation of ANG II based on these series.…”

Enantioselective Synthesis of 2‐(2‐Arylcyclopropyl)glycines: Conformationally Restricted Homophenylalanine Analogs

“…± Conformationally restricted a-amino acids [1] are important tools for studying the spatial requirements for receptor affinity and the biological activity of natural amino acids and peptides [2]. Replacement of natural amino acids in bioactive peptides by conformationally restricted amino acids has led to a better understanding of their bioactive conformations [3] [4]. Since l-Glu is a major neurotransmitter in the mammalian central nervous system, its mimetics are of possible interest in studies on (and eventually for the treatment of) pathological processes such as Alzheimer×s or Huntington×s disease, as well as Parkinsonism or neuronal damage resulting from cerebral ischemia and epilepsy [5].…”