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Synthèse et étude des relations structure-activité d’analogues trifluorométhylés du tripeptide GPE – CF3-GPE

Submission summary

Acute ischemic brain injury, enclosing hypoxic-ischemia is one of the major causes of death and long-term disability in adult life for which currently there is no promising therapy. Acute ischemic brain injury is related to considerable medical and non-medical costs. The increase of their incidence is likely to burden health systems in the future. Currently, acute ischemic can be treated by thrombolytics if patients can be registered to the clinic within three hours. One area of development of new treatment options is focused on neuroprotection. It is well known that the majority of neurons die several hours, even days following ischemic injuries. This evolution of cell loss is progressive and offers a window of opportunity for treatment intervention. Thus, the possibility of using potent neuronal rescue agents for enhancing neuronal protection as well as regeneration with exogenous administration of neurotrophic molecules appears as a powerful strategy. An important point is that this strategy can be extended to neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's diseases or multiple sclerosis. Insulin-like growth factor-1 (IGF-1), a 70 amino acids endogenous growth factor broadly distributed within the mammalian CNS, plays an essential role in normal growth and brain development. IGF-1 is a potent neurotrophic factor and can prevent neuronal death from several forms of ischemic injury in brain. In vivo particularly, IGF-1 has potent neuroprotective effects after hypoxic-ischemic injury and global ischemia in both the developing and the adult brain. In spite of its potent properties, the clinical application of IGF-1 can be problematic due to the limited capability to cross the blood-brain barrier (BBB) and the potential for mitogenic and metabolic effects. Nevertheless, IGF-1 is thought to be proteolytically cleaved in damaged brain tissues into the amino-terminal tripeptide glycine-proline-glutamate (GPE). So, IGF-1 seems to act as a prohormone for GPE. Unlike IGF-1, GPE neither binds to IGF-1 receptors nor has any neurotrophic effect, but it displays remarkable CNS activities. There is evidence that GPE exhibits neuromodulatory activities due to its ability to stimulate the potassium-evoked release of dopamine and acetylcholine. GPE shows high binding affinity for glutamate receptors (GluRs) and neuroprotective properties on different types of neurons from diverse induced injuries (e.g. hypoxia-ischemia, glutamate, quinolinic acid, etc.) both in vitro and in different animal models. Furthermore, GPE shows neuroprotective effects in different animal models on neurodegenerative processes, such as Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis and general aging-induced cognitive dysfunction. Because of its structural simplicity, and the relevance of both its binding affinity for GluRs and its neuroprotective activity after various brain injuries, GPE is considered as a promising starting point for the development of novel pharmaceutical agents for the treatment of CNS injuries and neurodegenerative disorders. Nevertheless, studies on metabolic stability have demonstrated that GPE was rapidly metabolised in plasma by proteases after intraperitoneal administration. While very short half-life in plasma limits the oral bioavailability of GPE, its hydrophilic nature (pKa = 8,6) can be a limitation in its central uptake particularly through transcellular pathway. These drawbacks hamper its pre-clinical and clinical trials and led to the development of numerous GPE analogues. This project deal with the synthesis of various trifluoromethylated GPE derivatives and the study of their structure-activity relationships. Thanks to it's unique conformational properties, proline plays an important role in GPE biological activity. The replacement of the proline by trifluoromethylated proline or pseudoproline should increase metabolic stability and lipophily allowing a better bioavailability Moreover, the induces conformational changes should lead to an enhanced neuroprotective activity. CF3 group will be introduced in 2- or 5- position regarding to the nitrogen. Thus, depending of the CF3 position, CF3-prolines and CF3-pseudoprolines share structural and conformational analogies with the most potent proline surrogates. In a first time, straightforward and highly selective routes for the synthesis of trifluoromethylated amino acids will be developed. In a second time new peptidic coupling methods will be studied in order to incorporate our CF3-AAs into the GPE sequence. Validation of these two milestone will represents an important technical and scientific breakthrough regarding the strong demand and few described methods. Finally, in order to obtain structure-activity relationships we will study conformations and neuroprotective activity of these fluorinated tripeptides. Biological tests will be performed in collaboration with professor Del Rio (Navarra University, Spain).

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The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

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