title: Rational design of triazololipopeptides analogs of kisspeptin inducing a long-lasting increase of gonadotropins.
abstract: New potent and selective KISS1R agonists were designed using a combination of rational chemical modifications of the endogenous neuropeptide kisspeptin 10 (KP10). Improved resistance to degradation and presumably reduced renal clearance were obtained by introducing a 1,4-disubstituted 1,2,3-triazole as a proteolysis-resistant amide mimic and a serum albumin-binding motif, respectively. These triazololipopeptides are highly potent full agonists of KISS1R and are >100 selective over the closely related NPFF1R. When injected in ewes with a quiescent reproductive system, the best compound of our series induced a much prolonged increase of luteinizing hormone release compared to KP10 and increased follicle-stimulating hormone plasma concentration. Hence, this KISS1R agonist is a new valuable pharmacological tool to explore the potential of KP system in reproduction control. Furthermore, it represents the first step to develop drugs treating reproductive system disorders due to a reduced activity of the hypothalamo-pituitary-gonadal axis such as delayed puberty, hypothalamic amenorrhea, and hypogonadotropic hypogonadism.
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Massimiliano
authors: M
authors: Beltramo
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Vincent
authors: V
authors: Robert
authors: ‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.
authors: Mathieu
authors: M
authors: Galibert
authors: ‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.
authors: Jean-Baptiste
authors: JB
authors: Madinier
authors: ‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.
authors: Philippe
authors: P
authors: Marceau
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Hugues
authors: H
authors: Dardente
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Caroline
authors: C
authors: Decourt
authors: §INSERM U690, Hôpital Robert Debré, 75019 Paris, France.
authors: Nicolas
authors: N
authors: De Roux
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Didier
authors: D
authors: Lomet
authors: ‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.
authors: Agnès F
authors: AF
authors: Delmas
authors: †UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247; Université François Rabelais Tours; IFCE), F-37380 Nouzilly, France.
authors: Alain
authors: A
authors: Caraty
authors: ‡Centre de Biophysique Moléculaire (CNRS UPR4301), Rue Charles Sadron, F-45071 Orléans Cedex 2, France.
authors: Vincent
authors: V
authors: Aucagne
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D059648:Kisspeptins / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D012756:Sheep; D014230:Triazoles / Q000097:blood / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; D012709:Serum Albumin; D014230:Triazoles; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D010447:Peptide Hydrolases