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Oligonucleotide analogues for biotechnology and material science

English title Oligonucleotide analogues for biotechnology and material science
Applicant Leumann Christian
Number 115913
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2007 - 31.03.2010
Approved amount 686'150.00
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Keywords (7)

RNA; oligonucleotides; DNA diagnostics; hydrophobic bases; oligonucleotide analogues; materials science; molecular beacons

Lay Summary (English)

Lead
Lay summary
The current grant application is divided into four sub-projects that all deal with the design, synthesis and the evaluation of novel chemically modified oligonucleotide analogues. Such analogues are of interest in DNA therapy, in DNA based diagnostics, as tools in biotechology and as architecural molecules in DNA based functional nanomaterials.
The first subproject deals with the development of an assay for the discovery of novel interacting DNA base analogues. The assay relies on reversible imine/hemiaminal chemistry of a chemically stable abasic site analogue with primary aromatic amins from a library, where the aromatic residue is exposed to a nucleobase of interest within a duplex structure. Matching arrangements with the target base are selected by a kinetically controlled chemical ligation step and the readout is performed by polyacrylamid gel electrophoresis. This assay may prove very useful in biotechnology, e.g. in the discovery of novel universal bases or bae-pairs for the expansion of the genetic alphabet.
The second subproject extends previous work on oligonucleotides in which the natural bases were replaced by simple aromatic units that recognize each other via interstrand stacking interactions. We expect that phenantrenes will show better stacking properties than the previously investigated biphenyls. We want to investigate the effect of peripheral substitution of the phenantrene units with electron donor and acceptor groups on the energy and charge transport properties. The results are of interest for applications in DNA diagnostics or for the design of charge separation devices in solar energy conversion.
Another subproject is concerned with the biological impact of abasic RNA. We want to investigate trans-lesion synthesis by reverse transcriptases on a synthetic abasic RNA template and compare the results with that on an abasic DNA template. Furthermore we want to investigate the fate of such RNA lesions in mRNA at the ribosome during translation. The results of this subproject will increase our general understanding of the biological impact of such RNA lesions that occur naturally.
The final subproject aims at an improvement of current molecular beacon technology. This technology is used for the sequence specific detection of RNA. We have shown before that replacement of beacon stems with homo-DNA greatly enhances DNA target selectivity. We now want to combine this property with enhanced signal production via homo-DNA templated synthesis of a fluorescent molecule upon RNA target recognition as well as via catalytic production of a fluorescent signal via protein complementation upon RNA target binding. This should lead to probes that might be able to detect low levels of RNA in vitro and eventually in vivo in a space- and time-resolved manner.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
121304 Purchase of a High-Performance Mass Spectrometer 01.09.2008 R'EQUIP
107692 Oligonucleotide analogues: Design, Synthesis and Applications in Biotechnology 01.04.2005 Project funding (Div. I-III)
130373 Chemically modified Oligonucleotides for Biotechnology and Material Sciences 01.04.2010 Project funding (Div. I-III)

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