Thiol-oligonucleotides for reversible chemical ligation and replication

• Applicant: Professor Dr. Günter von Kiedrowski
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279351736

Oligonucleotide templated syntheses offer a variety of applications in sequence specific programmable reactions. Chemically produced artificial oligonucleotide-systems were designed, which exist in gene diagnostics, drug screening or nano-constructs applications. Despite the wide variety of established ligation reactions of oligonucleotides, the number of reversible or switchable covalent linkage methods is limited. The project aims to contribute with a new ligation chemistry here. The ligation is based on thiol-disulfide exchange reactions that make use of the basic idea of the isosteric replacement of a 3-5-phosphodiester bond against a 3-5-disulfide bond. In this case, half-lives in the order of seconds could be achieved. The ligation is sequence selective, it can be shaped reversible or irreversible, and it proves to be sensitive to the redox state and pH-value. The project aims to exploit the full potential of the reversible disulfide linkage. A set of nucleic acid modifications is to be completed with the existent chemical synthesis methods and used in new ligation experiments. The feasibility of a directed chemical ligation, a template-directed polymerization and a dynamic DNA library is to be investigated. Furthermore, the thiol chemistry should be developed for new click-ligation reactions. The innovation of the project can be found in the configurability of the oligonucleotide ligation into reversible and irreversible direction, which can be used for the preparation of stable oligomeres out of dynamic systems. In combination with an already shown PCR amplification of disulfide oligonucleotides new applications in the context of biomedicine and DNA-nanotechnology can result.

• DFG Programme: Research Grants