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Synthèse par ingénierie métabolique d'oligosaccharides sialylés pour l'élaboration de glycoconjugués d'intérêt médical

Abstract : Sialylation is an important feature of glycolipids and glycoproteins of animal cell surfaces. Sialylatedmotifs are involved in many biological processes through lectin interactions or because of theirphysico-chemical properties. There is a great variety of sialylated structural motifs, and in manycases, there is a structure-relationship between the sialylated profile of and some pathologicprocesses. In cancer, there is an increase of sialylation including the apparition of newly andspecifically related sialylated structures belonging to the so-called tumor-associated carbohydrateantigens (TACA). Those structures present a particular interest, but their chemical or chemoenzymaticsynthesis is costly and quite unappropriated for preparative scale.This work addresses to the bacterial synthesis of sialylated motifs through the metabolic engineeringof Escherichia coli. The first part of the thesis deals with the biosynthesis of polysialylatedconjugatable motifs. Those motifs present various biological properties, such as an increase of thelife-time of therapeutic proteins; they also belong to the TACA family since over-expressed incancers. In addition, some of them are bacterial-specific motifs such as in pathogenic Neisseriameningitidis. Altogether, polysialylated conjugates can be useful for the synthesis of therapeuticdrugs and vaccines. The second part of the thesis describes a new way of producing sialylated Tn andTF carbohydrate antigens by metabolic engineering. The sialylTN motif was coupled to a peptidic andimmunogenic scaffold being a potential vaccine candidate, and its ability of raising specific antibodieswas assayed in mouse.
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Emeline Richard. Synthèse par ingénierie métabolique d'oligosaccharides sialylés pour l'élaboration de glycoconjugués d'intérêt médical. Médecine humaine et pathologie. Université Grenoble Alpes, 2017. Français. ⟨NNT : 2017GREAV007⟩. ⟨tel-01686785⟩

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