Synthèse et évaluation du métabolisme d'analogues immunogènes de la N-acétylgalactosamine (GalNAc)

Abstract : Glycans are often present at the cancerous cell surface in a modified form compared to healthy cells. However, these carbohydrate antigens don’t lead to an effective immune response. GalNAc is the first sugar attached to mucin type O-glycans and is thus a component of numerous tumor antigens. The aim of our work was to prepare synthetic GalNAc analogs able to be incorporated at the surface of cancer cell and into mucins synthesized by tumors in order to increase the immune response toward tumor glycans. We chemically synthesized GalNAc analogs to test them in vitro as substrates of enzymes involved in the mammalian GalNAc salvage pathway: a human galactokinase (GK2) and a human UDP-pyrophosphorylase (AGX1). The best candidates allowed the synthesis of the corresponding UDP-sugars further used to test the transfer of those analogs onto peptides using a bovine GalNAc transferase (ppGalNAc T1). We have shown that some synthetic analogs could be integrated in the GalNAc salvage pathway and O-linked to peptides. Immunological properties of the glycoconjugates thus formed were studied in mice after coupling to an immunostimulant protein (KLH). Moreover, mammalian cells were cultivated in the presence of these analogs in order to check their incorporation into glycoconjugates at the cell surface.
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Sabrina Pouilly. Synthèse et évaluation du métabolisme d'analogues immunogènes de la N-acétylgalactosamine (GalNAc). Sciences agricoles. Université d'Orléans, 2010. Français. ⟨NNT : 2010ORLE2058⟩. ⟨tel-00608103⟩

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