KISS project associates increasing livestock productivity and sustainability with decreased health risk. Our ambition is to develop a new treatment for reproduction control improving reproductive performance and reducing hormone use. This new treatment will be based on the development of analogs of the endogenous neuropeptide kisspeptin (Kp). A key objective of farming sustainable intensification is improvement of reproduction control in livestock. Our goal is to develop a new treatment to increase reproductive success and to obtain a superior control of birth timing while reducing hormone use and working cost. Current treatments face 4 major problems: i) use of hormone which could persist in the food and in the environment (e.g. progesterone derivatives). If more restrictive laws banning hormonal treatment will be approved, farmers will be obliged to apply less efficient and more time consuming methods leading to income reduction. This could render economically untenable the management of small farm and results in a dramatic drop of their number causing a deconstruction of local social tissue. ii) sanitary risk due to potential diseases transmission (i.e. use of equine Chorionic Gonadotropin (eCG), also named PMSG for pregnant mare’s serum gonadotrophin, extracted from blood serum), iii) immunological response against eCG that affects efficacy of ensuing treatments, and iv) suboptimal efficiency. To address these problems we designed a 1st generation of Kp analogs. Tests in sheep showed that these analogs are active at extremely low doses (tens of µg). Consequently any potential food contaminant issued from Kp analogs would be present in very low amount. In addition, thanks to their peptide nature, Kp analogs will be timely degraded and their inactive building block (simple amino acids) would be rapidly recycled or excreted. Furthermore, preliminary experiments in ewe showed that our 1st generation Kp analogs are superior to eCG in synchronizing ovulation and suggest that they may also improve efficiency. These results imply that replacement of eCG by Kp analogs is foreseeable. This would be by itself a major improvement eliminating sanitary risks and immunogenic liability. To complete the proof of concept tests to induce ovulation in sheep during the non breeding season are planned. Nonetheless, to assure an optimal response we anticipate the need to improve pharmacokinetics and pharmacodynamics of our 1st generation analogs. Therefore, we will develop a 2nd generation of molecules with refined pharmacokinetics and pharmacodynamics optimally suited for management of livestock reproduction. On the other hand, relevant features of Kp system, that may have an impact on Kp analogs efficacy, have been poorly investigated (e.g. receptor desensitization mechanisms, existence of functionally selective agonists, precise distribution of Kp receptor, etc). The lack of a sufficient portfolio of Kp receptor ligands with varied chemical structures and pharmacological profiles (partial agonists, antagonists, and biased agonists) largely account for the paucity of information on these topics. Our chemistry effort is generating a series of analogs with different chemical structures, highly selective and with distinct pharmacological profiles. We have the unique opportunity to exploit these new pharmacological tools, and eventually modify them to create antagonists, to better understand Kp system properties. This information will represent an important advance in basic science and will help the design of optimized analogs. Finally an added value of Kp analogs could be their use as a first step to develop new therapeutic agents to treat human diseases. To summarize, the objectives of the present project are 1) to develop a 2nd generation of Kp analogs 2) to ameliorate livestock reproduction management and 3) to advance our understanding of Kp system physiological functions.