Design, synthesis and investigation of substituted oligonucleotides for the regulation of gene expression

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Project objective

Research objectives and content Many human diseases arise from the dysfunction of genes. Oligonucleotides, which can form complexes with RNA or DNA by complementary base pairing, represent a new class of potential therapeutic agents for such diseases, acting directly on the nucleic acids. However, problems as the low stability of oligonucleotides in biological media, the poor penetration of oligonucleotides into cells and the reversibility of complex formation disturb the practical applications of oligonucleotides. Chemical modification of oligonucleotides, which will be the main objective of this project, could, at least partially, contribute to the resolution of these problems.The objectives of the research work will be: a)The attachment of a minor-groove-binding ligand to an oligonucleotide-intercalator conjugate (structure A), a novel and improved strategy for increasing the stability of oligonucleotide-DNA complexes.Oligonucleotide - L - intercalator - minor groove ligand (major-groove ligand)b)The employment of particular peptides as minor-groove ligands, which could exhibit several additional beneficial functions, such as a more effective internalization of the oligonucleotide or an extended range of recognition sequences. c)Synthesis of oligonucleotide-intercalator conjugates and testing for their ability to recruit topoisomerases (and, | possibly, other DNA-cleaving enzymes) for site-directed DNA damage.d)Elaboration of a reliable and versatile scheme for the modification of non-protected oligonucleotides which could be applied to a large variety of different ligands.e)The synthesized products will be tested in the appropriate system for their anti-sense or anti-gene effects. Links with industry / industrial relevance (22): Prof Claude Helene, the supervisor is a scientific director of Rhone Poulenc Rorer.Contracts with non-industrial and state research organizations:ANRS (Agence Nationale de la Recherche sur le SIDA), ARC (Association de la Recherche sur Cancer), League contre cancer. The laboratory of Biophysics includes two Units of state research organisations: U-201 INSERM (Institut National de la Sante et de la Recherche Medicale) and URA-48 I CNRS (Centre National de la Recherche Scientifique).

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Participants

• MUSEUM NATIONAL D'HISTOIRE NATURELLE · PARISCoordinatorFrance

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