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Synthèse de nouveaux détergents extractants et stabilisants des protéines membranaireset synthèse de dérivés d'aurones comme inhibiteurs d'ABCC2

Abstract : Understanding of tridimensional structure of membrane proteins (MPs) is crucial in medicinal chemistry and biochemistry. To maintain them in solution and consequently to prevent them from aggregation for structural and functional studies, utilization of detergents is indispensable. However, the conformation of MPs in complex with detergents could be very different from its membrane-embedded one. We synthetized new family of detergents, in which the incorporated carboxylates could generate a network of salt-bridges with basic-residue-enriched region of MPs, confer tighter interactions which could preserve their structural integrity. The detergents in which the glycoconjugation was achieved by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction showed remarkable capacity to extract, stabilize and crystallize studied PMs. On the other hand, novel inhibitors of ABCC2, a non-crystallized MP to date, were identified by screening: the 2-indolylmethylenebenzofuranones. Such compounds could be considered as useful tools to further investigate the role of ABCC2 in the pharmacokinetics of drugs.
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Kim-Anh Nguyen. Synthèse de nouveaux détergents extractants et stabilisants des protéines membranaireset synthèse de dérivés d'aurones comme inhibiteurs d'ABCC2. Biochimie [q-bio.BM]. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV043⟩. ⟨tel-01685485⟩

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