Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(Ⅲ) Schiff base conjugate

摘要

A transition metal complex targeted for the inhibition of a subset of zinc finger transcription factors has been synthesized and tested in Xenopus laevis. A Co(Ⅲ) Schiff base complex modified with a 17-bp DNA sequence is designed to selectively inhibit Snail family transcription factors. The oligonucleotide-conjugated Co(Ⅲ) complex prevents Slug, Snail, and Sip1 from binding their DNA targets whereas other transcription factors are still able to interact with their target DNA. The attachment of the oligonucleotide to the Co(Ⅲ) complex increases specificity 150-fold over the unconjugated complex. Studies demonstrate that neither the oligo, or the Co(Ⅲ) Schiff base complex alone, are sufficient for inactivation of Slug at concentrations that the conjugated complex mediates inhibition. Slug, Snail, and Sip1 have been implicated in the regulation of epithelial-to-mesenchymal transition in development and cancer. A complex targeted to inactivate their transcriptional activity could prove valuable as an experimental tool and a cancer therapeutic.