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Synthesis of trifunctional PNA-benzophenone derivatives for mitochondrial targeting, selective DNA binding, and photo-cross-linking

Lookup NU author(s): Dr Gunther Ross, Dr Paul Smith, Emeritus Professor Doug Turnbull, Professor Robert Lightowlers

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Abstract

Mutations in mitochondrial DNA (mtDNA) cause a variety of human pathologies. In many patients, mutated and wild-type mtDNAs coexist in the same cell, a situation termed mtDNA heteroplasmy. In the absence of standard therapies for these disorders, a genetic strategy for treatment has been proposed whereby replication of mutated mtDNA is inhibited by the selective hybridization of a nucleic acid derivative, allowing propagation of the wild-type genome and correction of the associated defects. To allow for selective binding under physiological conditions, peptide nucleic acids (PNA) are being used. Two other problems, however, have to be resolved: mitochondrial import and attachment of the PNA to the target DNA to inhibit replication. Mitochondrial localization can be achieved by the addition of a caged lipophilic cation and addition of a photo-cross-linking reagent should facilitate covalent attachment. We therefore report the synthesis of benzophenone-PNA derivatives carrying a triphenylphosphonium moiety and demonstrate irreversible binding selectivity between two DNA molecules that differ by a single nucleotide.

Publication metadata

Author(s): Ross GF, Smith PM, McGregor A, Turnbull DM, Lightowlers RN

Publication type: Article

Publication status: Published

Journal: Bioconjugate Chemistry

Year: 2003

Volume: 14

Issue: 5

Pages: 962-966

Print publication date: 01/09/2003

ISSN (print): 1043-1802

ISSN (electronic): 1520-4812

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/bc034050f

DOI: 10.1021/bc034050f

PubMed id: 13129399

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