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.
Highlights
Suboptimal reproduction in livestock and reproductive disorders in humans are problems that typically share a common cause: an inadequate activity of the hypothalamus-pituitary axis leading to an insufficient secretion of gonadotropins
In the present work we focused on two additional modifications in order to obtain a molecule suited for a preclinical proof of concept: introduction of the albumin-binding motif on the N-terminal amine of the triazolopeptide in place of the acetyl group of C2, rather than on the amine of the side chain of a lysine, and ω-methylation of Arg[9]
The present work discloses the synthesis of a Kp10 analog (C6) capable, following progestogen priming, of inducing fertile ovulation in ewes after a single intramuscular injection
Summary
Suboptimal reproduction in livestock and reproductive disorders in humans are problems that typically share a common cause: an inadequate activity of the hypothalamus-pituitary axis leading to an insufficient secretion of gonadotropins (luteinizing hormone, LH, and follicle stimulating hormone, FSH). In ewes during the non-breeding season, a condition characterized by low levels of circulating gonadotropins and resembling gonadotropic deficiency observed in some human pathology, a continuous perfusion of Kp10 induced ovulation[2] This is in line with the restoration of gonadotropin pulsatility following continuous Kp10 infusion in patients affected by hypogonadotropic hypogonadism (HH), induced by loss-of-function mutation in neurokinin B (NKB) or its receptor (TAC3R)[3]. In juvenile monkeys (Macaca mulatta) repeated hourly administration of Kp10 over a 48 hours period triggered LH and FSH release suggesting that the transition from juvenile to pubertal state is controlled by KiSS1R activation[6]. Further supporting this observation chronic central administration of Kp10 in female rats induced an advanced vaginal opening[7]. The design of molecules with improved pharmacological profile, capable of producing the same effect after a single intramuscular injection, would represent a key advance towards clinical and field applications
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