Template-Directed Cross-Linking of Oligonucleotides: Site-Specific Covalent Modification of dG-N7 within Duplex DNA

摘要

The interaction of small molecules with DNA is a fundamental mechanism in the chemotherapy of cancer and viral diseases. Although conventional small molecule drugs have proven effective as antitumor and antiviral agents, these compounds typically lackunique sequence-selective binding . In contrast, oligonucleotides can exploit the recognition elements inherent in Watson-Crick or Hoogsteen base-pairing to target specific information contained within a DNA or mRNA molecule, thereby potentially achieving unique sequence selectivity. We describe our preliminary studies on the use of oligonucleotide probes to direct chemically reactive functionality to targeted sequences of nucleic acids. In previous approaches to the problem of sequence selective covalent modification of oligonucleotides, groups containing reactive functionality have been attached to short oligonucleotides complementary to discrete sequences of single- or double-stranded DNA. Duplex (or triplex) formation delivers reactive functionality to the targeted sequence of the oligonucleotide. Herein, we describe methods to tether chemically reactive functionality within a targeted oligonucleotide sequence, and we report the high-yielding covalent modification of specific functional groups on the target oligomer. We have also examined the sequence-dependence of the covalent bond formation.