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Inhibition d'interactions protéine-protéine par des foldamères mixtes oligoamide/oligourée

Abstract : Protein-protein interactions (PPI) have a key role in physiological processes. The inhibition of these PPI may lead to new therapeutic strategies. Secondary structures in α-helix are frequently involved in protein interactions where they may contribute significantly to binding. Designing molecules which mimic the helical motif for protein surface recognition and inhibition of the natural partner represents an innovative path to discover new drug candidates. Aliphatic urea oligomers, a class of foldamers that adopt a well-defined H-bonded helical secondary structure with good similarity to the α-helix have been proposed as possible α-helix mimics to inhibit protein-protein interactions. The first part of this PhD project was dedicated to the design and synthesis of oligoureas and oligourea/α-peptide chimeras for specific protein surface recognition. We have selected the vitamin D receptor as a potential target, mainly because (i) it is therapeutically relevant; (ii) its protein partner (coactivators) interact through a short region which adopts an α-helical structure upon binding and (iii) structures at atomic resolution were available to enable the design of effective mimetics. In the second part, we investigated methods to generate foldamer covalent dimers that could potentially be used to cover larger interaction surfaces. The rationale is that the binding interface is often more complex than a single helix and may involve tertiary and quaternary structures such as coiled coils which in turns may also serve as a basis for the design of new classes of inhibitors.
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Submitted on : Tuesday, April 13, 2021 - 1:03:35 AM
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  • HAL Id : tel-03196598, version 1



Léonie Cussol. Inhibition d'interactions protéine-protéine par des foldamères mixtes oligoamide/oligourée. Chimie organique. Université de Bordeaux, 2018. Français. ⟨NNT : 2018BORD0394⟩. ⟨tel-03196598⟩



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