Shape-selective binding of geometrically-constrained bis-distamycins to a DNA duplex and a model Okazaki fragment of identical sequence

The binding of ligands to nucleic acids is of great interest for the contro l of gene expression and other nucleic acid mediated processes. We have eva luated the binding of several geometrically-constrained bis-distamycins to a model Okazaki fragment [OKA], or a DNA duplex having identical base seque nce [DD], using gel-shift assays, optical spectroscopy and differential sca nning calorimetry. In the case of covalent attachment of two distamycins to a central benzene ring, a similar binding profile was observed for [DD] as was observed for [OKA] (para binds [K-app > 10(6) M-1], meta binds only we akly). For a central pyridyl ring, however, clear distinction between the b inding to [DD] and binding to [OKA] was observed. While none of the three m eta isomers having a central pyridyl ring bound [OKA], two of them (MT-17 a nd MT-12) bound [DD] [K-app > 10(6) M-1]. These results demonstrate subtle differences in lexitropsin shape and placement of electronegative atoms may result in selective binding to a nucleic acid duplex based both on base se quence and chemical composition. Selective binding to DNA duplexes may be u seful for designing ligands that regulate transcription, but do not interfe re in other nucleic acid mediated processes.