Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Asami, Taichi; Nishizawa, Naoki; Ishibashi, Yoshihiro; Nishibori, Kimiko; Nakayama, Masaharu; Horikoshi, Yasuko; Matsumoto, Shimpei; Yamaguchi, Masashi; Matsumoto, Hirokazu; Tarui, Naoki; Ohtaki, Tetsuya; Kitada, Chieko

doi:10.1016/j.bmcl.2012.08.069

Cited by 29 publications

(39 citation statements)

References 43 publications

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“…Using this method, stability studies demonstrated that the peptide is rapidly degraded with a half-life of 1.7 min at 37 8C, the main degradation product being the N-terminal tyrosine-deleted peptide (Liu et al 2013). It is also worth noting that Arg9 methylation confers greater resistance of the peptide to trypsin while improving its agonistic potency (Asami et al 2012).…”

Section: Structure-activity Relationships and Evolution Of Kisspeptinsmentioning

confidence: 99%

“…In contrast, substitution of some amino acids of the N-terminal end with their D-enantiomers can improve the peptide activity and/or its resistance to proteases. For instance, replacement of Trp3 by D-Trp yields to a compound with high metabolic stability in serum and good agonistic activity (Asami et al 2012). Similarly, substitution of Tyr1 by D-Tyr increases the biological activity of the peptide in vivo (Curtis et al 2010).…”

Section: Structure-activity Relationships and Evolution Of Kisspeptinsmentioning

confidence: 99%

“…7; Kotani et al 2001, Muir et al 2001, Ohtaki et al 2001, Asami et al 2012. These studies, which used heterologous cell models, transfected with the rat or human KissR1 (CHO-K1 (Kotani et al 2001), HEK293 (Muir et al 2001), and B16-BL6 (Ohtaki et al 2001)), showed that in mammals, the phospholipase C (PLC)/protein kinase C (PKC)/MAPK pathway was activated (for reviews Castaño et al (2009) and Pinilla et al (2012)).…”

Section: Signaling Pathways In Mammalsmentioning

confidence: 99%

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MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

Pasquier¹,

Kamech²,

Lafont³

et al. 2014

Journal of Molecular Endocrinology

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Following the discovery of kisspeptin (Kiss) and its receptor (GPR54 or KissR) in mammals, phylogenetic studies revealed up to three Kiss and four KissR paralogous genes in other vertebrates. The multiplicity of Kiss and KissR types in vertebrates probably originated from the two rounds of whole-genome duplication (1R and 2R) that occurred in early vertebrates. This review examines compelling recent advances on molecular diversity and phylogenetic evolution of vertebrate Kiss and KissR. It also addresses, from an evolutionary point of view, the issues of the structure-activity relationships and interaction of Kiss with KissR and of their signaling pathways. Independent gene losses, during vertebrate evolution, have shaped the repertoire of Kiss and KissR in the extant vertebrate species. In particular, there is no conserved combination of a given Kiss type with a KissR type, across vertebrate evolution. The striking conservation of the biologically active ten-amino-acid C-terminal sequence of all vertebrate kisspeptins, probably allowed this evolutionary flexibility of Kiss/KissR pairs. KissR mutations, responsible for hypogonadotropic hypogonadism in humans, mostly occurred at highly conserved amino acid positions among vertebrate KissR. This further highlights the key role of these amino acids in KissR function. In contrast, less conserved KissR regions, notably in the intracellular C-terminal domain, may account for differential intracellular signaling pathways between vertebrate KissR. Cross talk between evolutionary and biomedical studies should contribute to further understanding of the Kiss/KissR structure-activity relationships and biological functions.

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Section: Structure-activity Relationships and Evolution Of Kisspeptinsmentioning

confidence: 99%

Section: Structure-activity Relationships and Evolution Of Kisspeptinsmentioning

confidence: 99%

Section: Signaling Pathways In Mammalsmentioning

confidence: 99%

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MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

Pasquier¹,

Kamech²,

Lafont³

et al. 2014

Journal of Molecular Endocrinology

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“…However, its in vitro EC 50 value is more than 0.1 m M and the GnRH-releasing activity in vivo remains to be confirmed. On the other hand, short-form peptide agonist analogs of Kp-10 have been reported by us and other investigators [31,[33][34][35] .…”

Section: Kiss1r Agonistsmentioning

confidence: 99%

“…Indeed, Kp-10 derivatives with D -Tyr 45 showed acceptable activity and evaded N-terminal degradation, and the residual ratio of an analog with D -Tyr 45 and Arg(Me) 53 was highly improved to 18.1% after 1 h of incubation in mouse serum. However, several metabolites were still observed in the electrospray ionization mass spectrometry spectra, including products of cleavage between Trp 47 -Asn 48 , Phe 50 -Gly 51 , and Gly 51 -Leu 52 [33] . 51 showed improved metabolic stability but reduced in vitro agonistic activity.…”

Section: -Asn 46mentioning

confidence: 99%

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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Neuropeptide derivatives to regulate the reproductive axis: Kisspeptin receptor (KISS1R) ligands and neurokinin‐3 receptor (NK3R) ligands

Oishi

Fujii

2016

Biopolymers

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Recent research has indicated pivotal roles for neuropeptides and their cognate receptors in reproductive physiology. Kisspeptins are RF-amide neuropeptides that stimulate gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus. Neurokinin B (NKB) is a member of the tachykinin family of neuropeptides and positively regulates pulsatile GnRH secretion. These peptides are coexpressed in kisspeptin/NKB/Dyn (KNDy) neurons of the arcuate nucleus, where they contribute to the regulation of puberty onset and other reproductive functions. In this review, the design of peptide ligands for the kisspeptin (KISS1R) and neurokinin-3 (NK3R) receptors are described. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 588-597, 2016.

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Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides

Cited by 29 publications

References 43 publications

MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

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

Neuropeptide derivatives to regulate the reproductive axis: Kisspeptin receptor (KISS1R) ligands and neurokinin‐3 receptor (NK3R) ligands

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