title: A synthetic kisspeptin analog that triggers ovulation and advances puberty.
abstract: The neuropeptide kisspeptin and its receptor, KiSS1R, govern the reproductive timeline of mammals by triggering puberty onset and promoting ovulation by stimulating gonadotrophin-releasing hormone (GnRH) secretion. To overcome the drawback of kisspeptin short half-life we designed kisspeptin analogs combining original modifications, triazole peptidomimetic and albumin binding motif, to reduce proteolytic degradation and to slow down renal clearance, respectively. These analogs showed improved in vitro potency and dramatically enhanced pharmacodynamics. When injected intramuscularly into ewes (15 nmol/ewe) primed with a progestogen, the best analog (compound 6, C6) induced synchronized ovulations in both breeding and non-breeding seasons. Ovulations were fertile as demonstrated by the delivery of lambs at term. C6 was also fully active in both female and male mice but was completely inactive in KiSS1R KO mice. Electrophysiological recordings of GnRH neurons from brain slices of GnRH-GFP mice indicated that C6 exerted a direct excitatory action on GnRH neurons. Finally, in prepubertal female mice daily injections (0.3 nmol/mouse) for five days significantly advanced puberty. C6 ability to trigger ovulation and advance puberty demonstrates that kisspeptin analogs may find application in the management of livestock reproduction and opens new possibilities for the treatment of reproductive disorders in humans.
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: C
authors.initials: C
authors.lastname: Decourt
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: V
authors.initials: V
authors.lastname: Robert
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: K
authors.initials: K
authors.lastname: Anger
authors.affiliation: Centre de Biophysique Moléculaire (CNRS UPR 4301) F-45071 Orléans cedex 2, France.
authors.forename: M
authors.initials: M
authors.lastname: Galibert
authors.affiliation: Centre de Biophysique Moléculaire (CNRS UPR 4301) F-45071 Orléans cedex 2, France.
authors.forename: J-B
authors.initials: JB
authors.lastname: Madinier
authors.affiliation: Centre for Neuroendocrinology, PO Box 913, University of Otago School of Medical Sciences Dunedin 9054, New Zealand.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: H
authors.initials: H
authors.lastname: Dardente
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: D
authors.initials: D
authors.lastname: Lomet
authors.affiliation: Centre de Biophysique Moléculaire (CNRS UPR 4301) F-45071 Orléans cedex 2, France.
authors.forename: A F
authors.initials: AF
authors.lastname: Delmas
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: A
authors.initials: A
authors.lastname: Caraty
authors.affiliation: Centre for Neuroendocrinology, PO Box 913, University of Otago School of Medical Sciences Dunedin 9054, New Zealand.
authors.forename: A E
authors.initials: AE
authors.lastname: Herbison
authors.affiliation: Centre for Neuroendocrinology, PO Box 913, University of Otago School of Medical Sciences Dunedin 9054, New Zealand.
authors.forename: G M
authors.initials: GM
authors.lastname: Anderson
authors.affiliation: Centre de Biophysique Moléculaire (CNRS UPR 4301) F-45071 Orléans cedex 2, France.
authors.forename: V
authors.initials: V
authors.lastname: Aucagne
authors.affiliation: UMR Physiologie de la Reproduction et des Comportements (INRA, UMR85; CNRS, UMR7247, Université François Rabelais Tours, IFCE) F-37380 Nouzilly, France.
authors.forename: M
authors.initials: M
authors.lastname: Beltramo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001947:Breeding / Q000379:methods; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010060:Ovulation / Q000187:drug effects* / Q000235:genetics; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1 / Q000172:deficiency / Q000235:genetics*; D012098:Reproduction / Q000187:drug effects* / Q000235:genetics; D027724:Reproductive Techniques, Assisted; D012741:Sexual Maturation / Q000187:drug effects* / Q000235:genetics; D012756:Sheep
chemical_list: C491407:Kiss1 protein, mouse; D059648:Kisspeptins; D057786:Peptidomimetics; D020033:Protein Isoforms; D000074502:Receptors, Kisspeptin-1; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone