title: Shape-selective binding of geometrically-constrained bis-distamycins to a DNA duplex and a model Okazaki fragment of identical sequence.
abstract: The binding of ligands to nucleic acids is of great interest for the control of gene expression and other nucleic acid mediated processes. We have evaluated the binding of several geometrically-constrained bis-distamycins to a model Okazaki fragment [OKA], or a DNA duplex having identical base sequence [DD], using gel-shift assays, optical spectroscopy and differential scanning 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 weakly). For a central pyridyl ring, however, clear distinction between the binding to [DD] and binding to [OKA] was observed. While none of the three meta isomers having a central pyridyl ring bound [OKA], two of them (MT-17 and 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 sequence and chemical composition. Selective binding to DNA duplexes may be useful for designing ligands that regulate transcription, but do not interfere in other nucleic acid mediated processes.
authors.affiliation: Biochemistry Department, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Gmeiner
authors.forename: W
authors.initials: W
authors.lastname: Cui
authors.forename: S
authors.initials: S
authors.lastname: Sharma
authors.forename: A M
authors.initials: AM
authors.lastname: Soto
authors.forename: L A
authors.initials: LA
authors.lastname: Marky
authors.forename: J W
authors.initials: JW
authors.lastname: Lown
mesh_terms: D001483:Base Sequence; D002152:Calorimetry, Differential Scanning; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004214:Distamycins / Q000138:chemical synthesis / Q000378:metabolism*; D008024:Ligands; D015394:Molecular Structure; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013696:Temperature; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D004214:Distamycins; D008024:Ligands; C421454:MT 12; C421455:MT 17; C022262:Okazaki fragments; C053654:lexitropsin; D009429:Netropsin; D004247:DNA