The minor groove of duplex DNA is important in enzyme and protein recognition. Naturally occurring polyamides, comprised of N-methylpyrrole di- or tri- peptides such as netropsin and distamycin, bind A-T rich sequences. These polyamides provide a paradigm in which tailor made specificity can be achieved. Polyamides containing N-methylimidazole monomers increase the sequence specificity of polyamides to include G-C base recognition. In tandem with N-methylpyrrole, sequence specificity can be achieved, with some exceptions. Our group has previously reported the ability of a neomycin-Hoechst 33258 (AT-rich DNA minor groove binder) conjugate to force neomycin to bind duplex DNA. While thermal stabilization of the DNA duplex was achieved, significant increases in binding affinity was not observed and high affinity binding of neomycin to DNA remained. A few years ago, our group identified aminoglycosides as lead candidates in groove based recognition of A-form nucleic acid structures. DNA, of GC-rich content, is known to tend toward A-form in the presence of cations. Polyamides (single as well as hairpin) were synthesized to target GC rich sequences and conjugated to neomycin. Neomycin specificity will be driven by the polyamide and the helical propensity for A-form will be achieved by varying the G-C content. We will present our preliminary reports on the targeting of such duplex DNAs.