title: Systematic synthetic and biophysical development of mixed sequence DNA binding agents.
abstract: It is now well established that, although only about 5% of the human genome codes for protein, most of the DNA has some function, such as synthesis of specific, functional RNAs and/or control of gene expression. These functional sequences open immense possibilities in both biotechnology and therapeutics for the use of cell-permeable, small molecules that can bind mixed-base pair sequences of DNA for regulation of genomic functions. Unfortunately very few types of modules have been designed to recognize mixed DNA sequences and for progress in targeting specific genes, it is essential to have additional classes of compounds. Compounds that can be rationally designed from established modules and which can bind strongly to mixed base pair DNA sequences are especially attractive. Based on extensive experience in design of minor-groove agents for AT recognition, a small library of compounds with two AT specific binding modules, connected through linkers which can recognize the G·C base pairs, were prepared. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that some pyridyl-linked compounds bind with the target sequence with sub-nanomolar KD, with very slow dissociation kinetics and 200 times selectivity over the related sequence without a G·C base pair. Interestingly, a set of compounds with AT module connected by different linkers shows cooperative dimer recognition of related sequences. This type of design approach can be expanded to additional modules for recognition of a wide variety of sequences.
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu.
authors.forename: Ananya
authors.identifier: http://orcid.org/0000-0001-5225-5089
authors.initials: A
authors.lastname: Paul
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu.
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu and Janssen Research and Development, 1400 McKean Rd, Spring House, PA 19477, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Nanjunda
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu and Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Abdelbasset A
authors.identifier: http://orcid.org/0000-0003-0664-5670
authors.initials: AA
authors.lastname: Farahat
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303-3083, USA. wdw@gsu.edu.
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D000578:Amidines / Q000737:chemistry*; D020029:Base Pairing; D001483:Base Sequence; D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D015374:Biosensing Techniques; D002942:Circular Dichroism; D006801:Humans; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D020349:Surface Plasmon Resonance
chemical_list: D000578:Amidines; D001562:Benzimidazoles; D054852:Small Molecule Libraries