Sequence-Specific and Synergistic Binding of Drugs to DNA

摘要

Our goals were to study the sequence specific and synergistic binding of three drugs having distinctly different binding modes: actinomycin D (ACTD), an intercalator with GpC sequence preference; chromomycin A3 (CHR), a guanine specific minor groove binder; and distamycin A (DST), an A.T specific minor groove binder. These results formed the bases for designing suitable sequences for the synergistic binding study commenced during the later part of the grant period. It was found that ACTD binds strongly and dissociates slowly at the dGpdc site with flanking T/T mismatches. An end-stacking model for the binding of ACTD to the non-Gpc-containing octamer d(OGTCGACG) was proposed. A recent observation of strong ACTD affinity for nearly complementary sequence D(CGXCGXCG) led us to speculate a possible single-strand binding mode with base- stacking on both sides of the ACTD chromophore. ACTD binding study with DNA oligomers of CXG repeats led to the finding that two ACTD molecules can bind tightly to two consecutive GpC sites separated by a single T/T mismatch, which was thought unlikely. Studies with DST led to a possible circular dichroic and kinetic differentiation of DNA binding modes of DST. Studies on the synergistic effects of drug binding, however, were less successful and may partially be the consequence of our sequence design.