KIRI

This project aims to design and physiologically use a new generation of pharmacological inhibitors targeting the ischemic stress through a protein we have recently identified as implicated in the resistance of tissues and organs to ischemia. The pre-clinical application that is concerned in the project is kidney transplantation. In human health the prevention of the consequences of an organic ischemic stress, due to oxygen deprivation, is one of the major concerns of clinicians. This stress occurs in pathological situations such as stroke, myocardial infarction, aortic surgery or organ transplantation. In the latter case, the ischemic stress is scheduled by the clinician who can therefore apply pre-conditioning protocols able to prepare the organ to resist against this stress. Unfortunately clinicians are lacking treatment against these ischemic pathologies due to the absence of identified pharmacological targets. A study conducted by Vigne et al. (2008) opened a new field of investigation by highlighting in Drosophila a new paradigm in tolerance to hypoxia. These authors have shown the primordial role of polyamines in oxygen sensitivity and they have identified the eukaryotic initiation factor 5A (eIF5A) and more particularly its activation step as being a pharmacological target of ischemic tolerance. We have transposed this new concept in mammals and have shown that the inhibition of eIF5A activation by GC7 (N-guanyl-1,7-diaminoheptane) protects renal function from an ischemic stress induced by temporary occlusion of the renal artery in rodent. This protective effect is consecutive to a decrease in oxidative phosphorylation activity associated to a decrease in oxidative stress. This pharmacological method of increasing ischemic tolerance via the targeting of the eIF5A hypusination step has been recently protected by an international patent (WO / 2012/010641). Applied to kidney transplantation at the pre-clinical level in pigs we have also shown that the pre-conditioning of the donor with GC7 allows a very clear improvement in the recovery of renal function of the recipient. eIF5A is an important element in the protein translation machinery and controls the specific synthesis of numerous proteins. To identify the primary target implicated in ischemic tolerance we conducted a differential proteomic study associated with mass spectrometry that allowed us to identify a candidate protein whose identity will not be revealed because of patent pending. Gene inhibition of this protein by siRNA or low affinity inhibitors has confirmed its role in ischemic tolerance either in vitro or in vivo. Our goal is to engineer, by organic synthesis, high affinity inhibitors for this protein target and, once characterized in vitro, to use them in vivo in a preclinical model of renal transplantation in pigs to ultimately test them in clinical trials. The first trials led with an home made specific inhibitor used for crystallography experiments of this protein in the nineties gave a positive result on the increase in anoxic tolerance in vitro confirming the relevance of the concept. On this project we have gathered a consortium of 3 laboratories with the necessary complementary expertise. UMR7370 Nice, inventor of the concept, expert in cell biology, renal physiology and oxidative stress management; UMR7272 (Nice Institute of Chemistry) specialized in organic synthesis of bio-active molecules; U1082 (University Hospital of Poitiers), specialist in renal transplantation at a preclinical level in pigs. We ask the ANR support 500k € for the three teams and for 3 years. In the future the development of this concept could apply to all pathological or clinical areas in which ischemic stress is involved.