Specific targeting of insect and vertebrate telomeres with pyrrole and imidazole polyamides

DNA minor groove-binding compounds (polyamides) that target insect and vert ebrate telomeric repeats with high specificity were synthesized. Base pair recognition of these polyamides is based on the presence of the heterocycli c amino acids pyrrole and imidazole, One compound (TH52B) interacts uniquel y and with excellent specificity (K-d = 0.12 nM) with two consecutive insec t-type telomeric repeats (TTAGG). A related compound, TH59, displays high s pecificity (K-d = 0.5 nM) for tandem vertebrate (TTAGGG) and insect telomer ic repeats, The high affinity and specificity of these compounds were achie ved by bidentate binding of two flexibly linked DNA-binding moieties. Epifl uorescence microscopy studies show that fluorescent derivatives of TH52B an d TH59 stain insect or vertebrate telomeres of chromosomes and nuclei sharp ly. Importantly, the telomere-specific polyamide signals of HeLa chromosome s co-localize with the immunofluorescence signals of the telomere-binding p rotein TRF1. Our results demonstrate that telomere-specific compounds allow rapid estimation of relative telomere length. The insect-specific compound TH52 was shown to be incorporated rapidly into growing Sf9 cells, underlin ing the potential of these compounds for telomere biology and possibly huma n medicine.