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Nouvelles méthodologies pour la synthèse totale de protéines

Abstract : Proteins play a crucial role in living organisms and in almost all biological mechanisms. The total chemical synthesis of proteins allows an atom by atom control of their structure and thus constitutes a powerful tool of investigation of biological processes involving these molecules. The solid phase peptide synthesis (SPPS) introduced by B. Merrifield in 1963 has revolutionized the field. Few years later, the discovery of chemical ligation methods and the development of peptide segment assembling strategies has been applied to the synthesis of many proteins. However, the difficulty in accessing large proteins reflects the absence of robust methods for the routine synthesis of such macromolecules.Novel synthetic methods based on Native Chemical Ligation and SEA/SeEA ligations have been developed in the frame of this thesis. In particular, I explored the interest of latent or in situ formed selenesters for facilitating the access to large proteins.The first part of this thesis describes the chemical properties of the bis(2-selenylethyl)amido (SeEA) group, i.e. the selenium analog of the bis(2-sulfanylethyl)amido (SEA) group, and its usefulness for accelerating peptide bond formation. This method was used for the synthesis of the NK1 protein (natural variant of the hepatocyte growth factor, HGF) constituted of 180 amino acids.The second part describes the in situ formation of selenesters through the design of novel selenium catalysts. These catalysts were used to accelerate the SEA ligation as well as the synthesis of thioester peptides from SEA peptides. Both reactions are central in the total synthesis processes developed in this thesis. Their usefulness is illustrated by the total synthesis of granulysin.The last part describes a method for the sequential ligation of peptide segments on a water compatible solid support which is complementary to the solution methods discussed above. This process has been automated and has a great potential for the automated chemical synthesis of proteins.
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Marine Cargoët. Nouvelles méthodologies pour la synthèse totale de protéines. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2017. Français. ⟨NNT : 2017LIL2S025⟩. ⟨tel-02441694⟩



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