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Towards an alternative to hormone treatments to control reproduction in small ruminants

Scientists from INRA and CNRS have created a pseudopeptide that could replace hormones of animal origin (eCG) in livestock reproduction management. This pseudopeptide is a stable analogue of kisspeptin and when administered via an intramuscular injection, triggers fertile ovulation in ewes. A finding with considerable potential for the management of livestock breeding!

Lambs born after treatment with C6 replacing the original figure. © Inra, M Beltramo
Updated on 09/05/2017
Published on 05/15/2017

Nowadays hormone treatments are widely employed by livestock breeders to control small ruminant reproduction and enable out of season reproduction, grouping births during short periods or speeding up genetic selection. This method is based on the administration of a glycoprotein hormone of animal origin, equine Chorionic Gonadotropin (eCG), in order to stimulate ovulation after an initial treatment with progestogen. The use of hormones in reproduction is associated with health and environmental risks (development of resistance to treatment, presence of residues in end-products or waste waters, etc.), and is under the strict regulation of the European Directive 96/22EC. To circumvent these problems new strategies to manage reproduction are in demand.

The search for hormone substitutes to control reproduction

Since several years, scientists at INRA and CNRS have been working on the development of substitutes for eCG, and have notably been exploring the use of kisspeptins. Kisspeptins are neuropeptides that play a central role in stimulating reproduction. Naturally present in the brain of mammals, these peptides trigger LH (luteinizing hormone) and FSH (follicle stimulating hormone) secretion through the stimulation of GnRH (gonadotropin-releasing hormone). However, the administration route (intravenous injection) and the metabolic instability of kisspeptins constitute major obstacles to their use in the field. 

Stabilising  kisspeptins

By introducing targeted chemical modifications, scientists in the Joint Research Unit for the Physiology of Reproduction and Behaviours (UMR PRC) and the Centre for Molecular Biophysics (UPR CBM; see contact list) have created a first generation of kisspeptin analogues that are more resistant to degradation and whose pharmacological profile is improved when compared to kisspeptins. An initial patent on these molecules was filed in 2013 (EP 2014/051886 - WO 2014/118318 A1). This project received support from the Région Centre-Val de Loire, (Reprokiss project, 2012-2015).

C6: a particularly interesting analogue

In the context of the Kiss and Capriss projects (see insert), scientists from the PRC, CBM, ICOA and the company Repropharm (see contact list) worked to optimise this first generation of molecules. They notably obtained a particularly effective compound that they called C6. It contains a 1,2,3-triazole heterocycle instead of a peptide bond particularly sensitive to protease degradation, a methyl group on arginine 9 and an albumin binding motif, palmitoyl-glutamate, at the N terminus. All these modifications procure greater resistance to degradation and prolonged in vivo action, as shown by their considerable efficacy in increasing plasma LH and FSH levels in ewes. In addition, C6 is active when administered by intramuscular injection and, at a dose of 15 nmol/animal in ewes pre-treated with a progestogen, has been able to induce fertile ovulations in both the breeding and non-breeding seasons. C6 could therefore represent a potential alternative to the use of eCG. Experiments are now under way to evaluate the possibility of using a kisspeptin analogue to replace progestogen hormones during the non-breeding season.
Complementary experiments with C6 have also shown its capacity to advance puberty in mice. These results, even though obtained in a rodent model, underline the potential of this analogue to manage reproduction during the whole lifespan of livestock.

Contact(s)
Scientific contact(s):

Other contact(s):
Associated Division(s):
Animal Physiology and Livestock Systems
Associated Centre(s):
Val de Loire

Find out more

  • M. Beltramo, V. Aucagne, A. Caraty, A. F. Delmas. Composés agonistes du KISS1R et leur utilisation pour induire l’ovulation chez les mammifères. French patent application no. 50858 filed on 31/01/2013. PCT/EP2014/051886, published as ref. WO2014118318, national phases in Europe, Canada, USA, Australia, Brazil.
  • M. Beltramo, V. Robert, M. Galibert, J.-B. Madinier, P. Marceau, H. Dardente, N. De Roux, D. Lomet, A. F. Delmas, A. Caraty, V. Aucagne Rational design of triazolo-lipopeptides analogues of kisspeptin inducing a long-lasting increase of gonadotrophins. The Journal of Medicinal Chemistry, 2015, 58, 3459−3470.
  • C. Decourt, V. Robert, K. Anger, M. Galibert, J.-B. Madinier, H. Dardente, D. Lomet, A. F. Delmas, A. Caraty, A. Herbison, X. Liu, G. Anderson, V. Aucagne, M. Beltramo A synthetic kisspeptin analog that triggers ovulation and advances puberty. Scientific Reports, 6, 26908; doi: 10.1038/srep26908 (2016)

ReproPharm

Set up in 2009 and based on the INRA site in Tours, ReproPharm is a young, innovative company working in the field of animal reproduction as it concerns sheep, goat, cattle and pig breeding. It provides to research professionals, breeding technicians and breeders with efficient solutions resulting from INRA know-how.

For more information: www.repropharm.com

For more information on the Kiss and Capriss projects

  • The Capriss project (2015-2018), funded by the Centre-Val de Loire Region to a value of €200,000 over a three-year period, is studying the effect of a kisspeptin analogue in goats. It should achieve proof of concept of the efficacy of this analogue in triggering ovulation during a period of anoestrus after a single injection. A second generation of optimised molecules for use in livestock will also be synthesised.
  • The Kiss project (2015-2019), funded by the ANR to a value of €600,000 over a four-year period, is focusing firstly on better understanding the functioning of kisspeptin receptors (distribution of these receptors, cellular pharmacology, etc.), and secondly on developing a second generation of optimised analogues. This project is notably using in silico modelling to screen potential ligands (molecular docking) and to guide the synthesis of new molecules before performing in vitro and in vivo tests.