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Synthèse et caractérisation de mimes de surfaces d'interaction protéine-protéine par voie d'assemblage combinatoire sur châssis spatialement adressable

Abstract : Targeting the protein-protein interaction surfaces to obtain inhibitors remains one of the most challenging area of the last decade. In that way, we designed and studied a new bi-functional synthetic template named RAFT. The core of the template is composed of a cyclic decapeptide scaffold presenting two distinct adressable domains. These allow the spatial separation of both functions of the template and prevent the molecules from the lower face to interfere with the targeting functions. In order to aim at the protein surfaces, a combinatorial assembly of four peptides on the upper face of the RAFT have been done. Thus, one can get all the possible surface combinations enabling an efficient targeting of the protein surfaces. The multiple presentation of peptides on the template was achieved through a convergent synthesis using efficient chimioselective oxime ligations. Concerning the substituents of the RAFT, four linear and four cyclic peptides, constraints by disulfide bridges, have been synthesized. The last present globally the same sequences except for two positions where the incorporation of different residues (Lys, Asp, Phe, Ser) confer different properties (charge, nature...). The use of those substituents have been done for distinct purposes : (i) the formation of GnRH-receptor mimetics and (ii) a more general targeting of protein surfaces. The total characterisation of the libraries was done using HPLC and LC-MS methods. Finally, the first biological evaluations on on several targets (GnRH, avidine, SHC-Grb2 interface) of those libraries gave encouraging results.
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https://tel.archives-ouvertes.fr/tel-00011547
Contributor : Sophie Plé <>
Submitted on : Monday, February 6, 2006 - 7:22:56 PM
Last modification on : Friday, November 6, 2020 - 3:48:20 AM
Long-term archiving on: : Saturday, April 3, 2010 - 8:19:25 PM

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  • HAL Id : tel-00011547, version 1

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Sophie Plé. Synthèse et caractérisation de mimes de surfaces d'interaction protéine-protéine par voie d'assemblage combinatoire sur châssis spatialement adressable. Autre. Université Joseph-Fourier - Grenoble I, 2006. Français. ⟨tel-00011547⟩

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