Interaction of the human topoisomerase I-DNA complex with oligo-1,3-thiazolecarboxamides and their oligonucleotide conjugates

Nonnatural thiazole-containing oligopeptides (TCOs) bind to the DNA minor g roove and inhibit the reaction catalyzed by human topoisomerase I(TopoI), T he effect is directly proportional to the number of thiazole monomers in TC O. Several TCOs with three or four thiazole monomers act 3-10 times more ef ficiently than distamycin A, a natural antibiotic containing pyrrole rings. Additional groups at the N and C termini only slightly affect TopoI inhibi tion by TCQ. The inhibitory effect of TCOs is higher than that of homo- or heterooligopeptides containing imidazole or pyrrole monomers, and the most potent are oligopeptide-oligonucleotide conjugates. The plausible causes of the different effects of distamycin and the nonnatural peptides on DNA rel axation catalyzed by TopoI are discussed.