Conformational modulation of DNA by polyamide binding: structural effects of f‐Im‐Py‐Im based derivatives on 5′‐ACGCGT‐3′. Issue 8 (19th June 2013)

• Record Type: Journal Article
• Authors: Wang, Shuo; Chai, Yun; Babu, Balaji; Satam, Vijay; Lee, Moses; David Wilson, W.
• Is Part Of: Journal of molecular recognition. Volume 26:Issue 8(2013:Aug.)
• Page Start: 331
• Page End: 340
• Publication Date: 2013-06-19
• Subjects: Molecular recognition -- Periodicals; Models, Molecular -- Periodicals; Molecular Conformation -- Periodicals; Molecular Sequence Data -- Periodicals; Molecular Structure -- Periodicals; Carrier Proteins -- Periodicals; 572.8
• DOI: 10.1002/jmr.2273
• Languages: English
• ISSNs: 0952-3499

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>The DNA sequence 5′‐ACGCGT‐3′ is in the core site of the Mlu 1 cell‐cycle box, a transcriptional element in the promoter region of human Dbf4 gene that is highly correlated with a large number of aggressive solid cancers. The polyamide formamido‐imidazole‐pyrrole‐imidazole‐amine<sup>+</sup> (f‐Im‐Py‐Im‐Am<sup>+</sup>) can target the minor groove of 5′‐ACGCGT‐3′ as an antiparallel stacked dimer and has shown good activity in inhibiting transcription factor binding. Recently, f‐Im‐Py‐Im‐Am<sup>+</sup> derivatives that involve different orthogonally positioned substituents were synthesized to target the same binding site, and some of them have displayed improved binding and pharmacological properties. In this study, the gel electrophoresis–ligation ladders assay was used to evaluate the conformational effects of f‐Im‐Py‐Im‐Am<sup>+</sup> and derivatives on the target DNA, an essential factor for establishing the molecular basis of polyamide–DNA complexes and their transcription factor inhibition. The results show that the ACGCGT site in DNA has a relatively wide minor groove and a B‐form like overall structure. After binding with f‐Im‐Py‐Im‐Am<sup>+</sup> derivatives, the DNA conformation is changed as indicated by the different mobilities in the gel. These conformational effects on DNA will at least help to point to the mechanism for the observed Mlu 1 inhibition activity of these polyamides. Therefore, modulating DNA transcription by locking the DNA shape or altering the minor groove geometry to affect the binding affinity of certain transcription factors is an attractive possible therapeutic mechanism for polyamides. Some of the substituents are charged with electrostatic interactions with DNA phosphate groups, and their charge effects on DNA gel mobility have been observed. Copyright © 2013 John Wiley & Sons, Ltd.</p> </abstract>