Conformational properties of azapeptides

Thormann, Michael; Hofmann, Hans‐Jörg

doi:10.1016/s0166-1280(98)00567-3

Cited by 67 publications

(72 citation statements)

References 44 publications

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“…This nitrogen substitution is believed to have little effect on the overall physicochemical profiles of these peptides; however, electronic repulsion between the adjacent nitrogen atoms has been suggested to induce type I and II b-turn conformations. [19][20][21][22][23][24][25][26][27][28][29][30][31] This b-turn geometry of aza amino acid-containing peptides may contribute to improve binding affinity of metastin analogs for KISS1R. NMR analysis of the metastin(45-54) analog in dodecylphosphocholine micelles showed that it contained several tight turn structures such as miscellaneous type IV b-turns (residues Asn 48 -Gly 51 and Gly 51 -Phe 54 ).…”

Section: Introductionmentioning

confidence: 99%

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Asami

Nishizawa

Ishibashi

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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Section: Introductionmentioning

confidence: 99%

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Asami

Nishizawa

Ishibashi

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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“…The replacement of Gly 51 with an azaGly residue, which involved a simple nitrogen atom replacement of the α-carbon on Gly 51 , improved KISS1R agonistic activity, presumably because of the change in the overall conformation of peptide analogs, thus avoiding enzymatic degradation [33] . This indicated that some β-turn conformations, which are reportedly observed in azapeptides [39][40][41] , may contribute to interactions with KISS1R. Moreover, incorporation of the azaGly 51 residue improved metabolic stability of Phe 50 -Gly 51 and Gly…”

Section: -Asn 46mentioning

confidence: 83%

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

Matsui¹,

Asami

2014

Neuroendocrinology

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The hypothalamic peptide kisspeptin (metastin), the endogenous ligand of the G protein-coupled receptor KISS1R, plays a critical role in controlling GnRH release from hypothalamic GnRH neurons and thereby regulates hypothalamic-pituitary-gonadal functions. Although the therapeutic potential of kisspeptin is attractive, its susceptibility to proteolytic degradation limits its utility. To overcome this, KISS1R agonists or antagonists as peptide analogs or small molecules have been investigated. Kisspeptin analogs have been most extensively studied by reducing the length of the peptide from the original 54 amino acids to 10 amino acids or less and by substituting key amino acid residues. Also, 2 investigational kisspeptin agonist analogs have been evaluated in clinical studies in men; in agreement with animal studies, abrupt elevations in gonadotropin and testosterone levels were observed as an acute effect, followed by rapid reductions in these hormones as a chronic effect. Some studies of small-molecule KISS1R antagonists have also been published. In this review, we present a brief overview on kisspeptin/KISS1R physiology in reproductive functions and summarize the available knowledge of both agonists and antagonists. We also focus on the kisspeptin agonist analogs by summarizing key pharmacological findings from both clinical and preclinical studies, and discuss their potential therapeutic utility.

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“…Introducing an N α generates two structural elements, hydrazine and a urea constituent, whose conformations are described by the peptide torsion angles ϕ and ψ (Fig. (2)) [19].…”

Section: Conformational Propertiesmentioning

confidence: 99%

“…The most interesting structural variation is associated with the hydrazine moiety. The conformations of hydrazine and its 1,2-diformyl derivative, which resemble the hydrazine moiety in azapeptides, were investigated by quantum chemical studies [19][20][21][22][23]. Calculations show that the global minimum energy structure of 1,2-diformyl hydrazine and its N-substituted derivatives is the nonplanar structure in which the nitrogen lone pairs are perpendicular to one another.…”

Section: Conformational Propertiesmentioning

confidence: 99%

Azapeptides as Pharmacological Agents

Zega¹

2005

Current Medicinal Chemistry

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Azapeptides, formed by replacing the C α of amino acid residues by nitrogen, are promising peptidomimetic compounds. Azaamino acids impart a unique conformational property to peptide structures because of the loss of chirality and reduction of flexibility of the parent linear peptide. The peculiar conformational properties make azaamino acids an attractive tool for drug design involving specific secondary structures in peptides and proteins. Additionally, since azapeptides are less susceptible to enzymatic breakdown by proteases, they may possibly lead to orally active drugs with longer duration of action. One of the advantages of azapeptides is their unproblematic synthesis allowing retention of the amino acid side chain. Azapeptides have been developed by several groups for the design of hormone analogues, protease inhibitors and active site titrants.

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Conformational properties of azapeptides

Cited by 67 publications

References 44 publications

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Effects and Therapeutic Potentials of Kisspeptin Analogs: Regulation of the Hypothalamic-Pituitary-Gonadal Axis

Azapeptides as Pharmacological Agents

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