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Etude des effets de la glycation sur les interactions protéine-ligand dans le cadre du diabète et de l’athérosclérose : la liaison entre l’albumine et le liraglutide et entre l’apolipoprotéine A1 et ses partenaires de liaison

Abstract : Protein-ligand interactions are involved in many biochemical processes. They are notably implicated in the role of transporter proteins in blood. Albumin, the most abundant plasma protein, and apolipoprotein A1 (ApoA1), which is the main component of high-density lipoprotein (HDL) belong to this class of proteins. In the context of diabetes, proteins are altered by glycation which leads to structural modifications and potentially affect their interactions.The first objective of this work was to determine the impact of albumin glycation on its binding to liraglutide, a drug increasingly used in the treatment of type 2 diabetes. Then, the second part of this work involved the production of recombinant functional human ApoA1 in order to study its interaction properties, in its lipid-free form or associated with phospholipids. The NMR (nuclear magnetic resonance) technique has been used on proteins previously labeled with fluorine (for liraglutide) or stable 13C/15N isotopes (for ApoA1). In addition, isothermal titration microcalorimetry (ITC), has been applied to the study of interactions with the advantage of not requiring any labeling. Various cloning strategies have been explored for the overexpression of ApoA1 in Clearcoli bacteria.The results demonstrate an alteration of the affinity of albumin for liraglutide in vitro and in vivo, depending on the degree of glycation. These results, supported by a lipidomic and peptide analysis, explain clinical observations concerning the decrease of efficacy of albumin-binding drugs in patients with poorly controlled diabetes. Regarding ApoA1, the choice of the fusion tag remains to be optimized, but both labeled and unlabeled ApoA1 were successfully overexpressed at high yields in a soluble form.
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  • HAL Id : tel-01880956, version 1

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Marie Angélique Gajahi Soudahome. Etude des effets de la glycation sur les interactions protéine-ligand dans le cadre du diabète et de l’athérosclérose : la liaison entre l’albumine et le liraglutide et entre l’apolipoprotéine A1 et ses partenaires de liaison. Santé. Université de la Réunion, 2018. Français. ⟨NNT : 2018LARE0009⟩. ⟨tel-01880956⟩

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