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Contenido archivado el 2024-04-30

Research of bis-specific inhibitors of telomerase - development of combinatorial synthesis and high throughput screening of oligonucleotide -peptide libraries

Objetivo



Research objectives and content
Telomeres are the repeated sequences of DNA, and associated protein, that occur at the 3' ends of eukaryotic chromosomes. They are synthesized by specialized DNA polymerase, telomerase, a ribonucleoprotein enzyme that uses an in-built RNA template. Current data link the activity of the enzyme telomerase to several forms of cancer. Specific inhibitors of telomerase are now needed to directly test this relationship, help understand the mechanism of telomerases and serve as lead compounds for potential future anti-cancer agents. The RNA-template portion of telomerase has been shown to be a target for antisense oligonucleotides. We aim to enhance the binding interaction substantially by the addition of a second binding interaction and propose to generate molecules bearing antisense component (DNA or peptide nucleic acids) directed at the RNA template of telomerase and also a pendent oligopeptide component to target the anchor site of telomerase.Since there is no structural information available on this second anchor site, we propose to employ combinatorial synthesis to identify lead compounds for telomerase inhibition. Combinatorial synthetic methodology will be developed to prepare libraries peptides conjugated to antisense DNA or PNA sequences. The DNA-peptide and PNA-peptide libraries will be screened to select potent telomerase inhibitors that will be characterised by quantitative biochemical and biophysical methods.
Training content (objective, benefit and expected impact)
My interest is to acquire during my postdoctoral position fresh knowledge ininnovatory field of combinatorial chemistry (synthesis and screening). The present project offers me also the opportunity to complete my scientific skills in oligonucleotide and peptide chemistry (PhD work : synthesis and study of antigene oligonucleotides directed against HIV-1). Furthermore, this project is likely to be of interest to number of prominent laboratories in my home country, where there has been a tradition of excellence in the field of nucleic acid chemistry and antisense research. This grant would help me acquire fresh state-of-the art technologies that will contribute to the existing expertise in France. Links with industry / industrial relevance (22)
Dr. Balasubramanian has been involved in a combinatorial chemistry collaboration with Zeneca since 1994. The collaboration has thus far involved aspect of both synthesis and screening. The advice and support of colleagues in the creening section of the pharmaceutical industry will be sought as required.

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Coordinador

University of Cambridge
Aportación de la UE
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Dirección
Lensfield Road
CB2 1EW Cambridge
Reino Unido

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