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Artificial insemination is widely employed by dairy farmers and, to a lesser extent, by those managing suckler herds. However, this technique, which enables the control of reproduction in livestock, requires the use of hormones to stimulate ovulation (hormones of animal origin, such as equine Chorionic Gonadotropine or eCG, and synthetic steroidal hormones). Using hormones has certain drawbacks for farmers (development by livestock of resistance to hormone treatments that could limit their efficacy, health risks associated with using hormones of animal origin), for consumers (presence of residues in animal products) and for the environment (release of hormones into the environment).

For several years now, scientists in the Joint Research Unit for Reproductive and Behavioural Physiology (PRC) have been working on substitutes for steroidal hormones by exploring the potential of targeting the kisspeptin system.  Kisspeptins are neurotransmitters which play a central role in stimulating reproduction.  In a highly competitive international research environment, the INRA team has been one of the pioneers in demonstrating this role.  Naturally present in the brain, these peptides activate the secretion of LH¹ and FSH² through GnRH³ release, but their metabolic instability prevents their application in the field. 

During an initial project (Reprokiss) funded by the Regional Council for Centre-Val de Loire, PRC scientists working with CNRS chemists developed kisspeptin analogues that were active at extremely low doses (of around 10 microgrammes per ewe) with a much longer duration of action than the natural substance (several hours instead of a few minutes).  In addition, these analogues supposedly break down into sub-units (mainly amino acids) that are without danger to humans or the environment. This first generation of analogues has since proved its efficacy in triggering ovulation in ewes, and these results prompted the filing of an initial patent (EP2014051886, WO2014118318).

INRA research scientists, in collaboration with the CPM (Centre for Molecular Biophysics, UPR 4301 CNRS - Université d’Orléans), ICOA (Institute of Organic  and Analytical Chemistry, UMR 7311 CNRS - Université d’Orléans) and ReproPharm are now pursuing optimisation  of the analogues and their potential applications in the context of two new projects:

• Capriss, funded (€200,000) by the Regional Council for Centre – Val de Loire over a three-year period, will be studying the effect of a kisspeptin analogue in goats. The goal is to obtain proof of concept in this species of the efficacy of this analogue in triggering ovulation with a single injection during the non-breeding season. In parallel, compounds will be optimised to enable their potential application in the field .  The estimated production costs for these compounds is very competitive when compared with current hormone treatments, and their efficacy should be superior.

• Kiss, funded (€600,000) by the French National Research Agency (ANR) over a four-year period, aims firstly, to better understand the activity of the kisspeptin system by studying its localisation and the pharmacology of kisspeptin receptors, and secondly to develop a second generation of even more efficient analogues by applying an innovative medicinal chemistry approach combining in silico and in vitro methods.  This project will notably use in silico modelling to screen potential ligands (molecular docking). Once synthesised, these structures will be tested in vitro and then in vivo. In addition to potential applications to the management of livestock reproduction, which is the primary target of the Kiss project, this work may also offer therapeutic opportunities to treat human disorders.

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¹ LH: luteinizing hormone
² FSH: follicle-stimulating hormone
³ GnRH: Gonadotropin-releasing hormone