Oligonucleotide-based telomerase inhibitors with a photoresponsive α-chloroaldehyde

Telomerase, a ribonucleoprotein, is a reverse transcriptase that uses telomerase RNA component (hTR) as a template to elongate telomeric DNA at the ends of chromosomes. This enzyme plays a critical role in oncogenic cellular transformation. Therefore, the telomerase is considered an attractive target for cancer therapy. In this study, we synthesized photo-cross-linking oligodeoxyribonucleotides (ODNs) with a photoresponsive α-chloroaldehyde (PCA) moiety at the 3′-end or the 5′-end of the ODNs and evaluated the inhibition efficiencies for telomerase activity. PCA-modified ODNs with a sequence complementary to the template RNA of telomerase inhibited telomerase activity upon UV irradiation, whereas those with scramble sequence showed no significant inhibition. The 50 % inhibitory concentration (IC₅₀) of PCA-modified ODN was significantly reduced by UV irradiation. These results indicate that PCA-modified ODN inhibits telomerase activity in a sequence-selective manner and that the inhibitory activity is enhanced by the cross-linking reaction following UV irradiation.