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Single-Core Agents for Therapeutics and Imaging – SATIN

Submission summary

Protein-Protein interactions (PPIs) are essential components of biological processes and have emerged as therapeutic targets of interest. The ability to control PPIs is highly challenging and new strategies for the development of efficient modulators are desirable. In the SATIN project, we propose the design of metallic Single core Agents for Therapeutics and ImagiNg based on Re(CO)3 moieties. Re(CO)3 units will constitute structural constraints to stabilize secondary structures in peptide mimics (ß-turn, a-helices) and will be used as central scaffolds for the design of small molecules to lock their functionalities in the correct orientation. They will concomitantly enable the detection and imaging of the resulting inhibitors in cells using fluorescence, IR and/or X-fluorescence imaging without any further labelling. This innovative approach simultaneously addresses the biological activity and the cellular penetration, quantification and localisation using a unique all-in-one object. It should thus bring new insights into the biological activity of the PPIs inhibitors and result in the identification of stable, potent and selective inhibitors of PPIs.
As a proof of concept in the course of this project, we will target the well-characterized interaction between the ubiquitination facilitator Keap1 and the transcription factor Nrf2. Disruption of this interaction is a promising approach to enhance the expression of endogenous antioxidant and free radical detoxification gene products regulated by Nrf2. Activation of Nrf2 leads to a coordinated antioxidant and anti-inflammatory response. Agents that disrupt this protein–protein interaction may thus be of beneficial outcome in a variety of diseases (cancer, diabetes, atherosclerosis, inflammatory and Alzheimer’s diseases) in which lowering of oxidative stress by protective genes plays an important therapeutic role.
This interdisciplinary project involves synthesis and synthetic methodology development, structural studies, biological evaluation by biophysical and cell-based assays and in-cells imaging. It requires the set-up of challenging imaging techniques and brings together researchers combining all the necessary expertise to carry it out successfully.

Project coordinator

Madame Helene Bertrand (Laboratoire des Biomolécules)

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.

Partner

LBM Laboratoire des Biomolécules

Help of the ANR 268,320 euros
Beginning and duration of the scientific project: September 2017 - 48 Months

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