Rational design of specific binding hairpin Py-Im polyamides targeting human telomere sequences.

Abstract

N-Methylpyrrole (Py)–N-methylimidazole (Im) polyamides are organic molecules that can recognize predetermined DNA sequences in a sequence-specific manner. Human telomeres contain regions of (TTAGGG)n repetitive nucleotide sequences at each end of chromosomes, and these regions protect the chromosome from deterioration or from fusion with neighboring chromosomes. The telomeres are disposable buffers at the ends of chromosomes that are truncated during cell division. Tandem hairpin Py–Im polyamide TH59, which recognizes human telomere sequences, was reported by Laemmli’s group in 2001. Here, we synthesized three types of Py–Im polyamides 1–3 based on TH59 for specific recognition of human telomere repeat sequences. Thermal melting temperature (Tm) measurements and surface plasmon resonance analysis were used to evaluate the abilities of the three types of Py–Im polyamides to discriminate between three kinds of DNA sequences. Significantly, the results showed that polyamides 1 and 2 have better affinities to TTAAGG than to TTAGGG. In contrast, polyamide 3 displayed good specificity to human telomere sequence, TTAGGG, as expected on the basis of Py–Im binding rules