title: Affinity and kinetic modulation of polyamide-DNA interactions by N-modification of the heterocycles.
abstract: Synthetic N-methyl imidazole and N-pyrrole containing polyamides (PAs) that can form "stacked" dimers can be programmed to target and bind to specific DNA sequences and control gene expression. To accomplish this goal, the development of PAs with lower molecular mass which allows for the molecules to rapidly penetrate cells and localize in the nucleus, along with increased water solubility, while maintaining DNA binding sequence specificity and high binding affinity is key. To meet these challenges, six novel f-ImPy*Im PA derivatives that contain different orthogonally positioned moieties were designed to target 5'-ACGCGT-3'. The synthesis and biophysical characterization of six f-ImPy*Im were determined by CD, ΔTM, DNase I footprinting, SPR, and ITC studies, and were compared with those of their parent compound, f-ImPyIm. The results gave evidence for the minor groove binding and selectivity of PAs 1 and 6 for the cognate sequence 5'-ACGCGT-3', and with strong affinity, Keq = 2.8 × 10(8) M(-1) and Keq = 6.2 × 10(7) M(-1), respectively. The six novel PAs presented in this study demonstrated increased water solubility, while maintaining low molecular mass, sequence specificity, and binding affinity, addressing key issues in therapeutic development.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Ramos
authors.forename: Balaji
authors.initials: B
authors.lastname: Babu
authors.forename: Sameer
authors.initials: S
authors.lastname: Chavda
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Adam
authors.initials: A
authors.lastname: Plaunt
authors.forename: Amanda
authors.initials: A
authors.lastname: Ferguson
authors.forename: Mia
authors.initials: M
authors.lastname: Savagian
authors.forename: Megan
authors.initials: M
authors.lastname: Lee
authors.forename: Samuel
authors.initials: S
authors.lastname: Tzou
authors.forename: Shicai
authors.initials: S
authors.lastname: Lin
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kiakos
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D001483:Base Sequence; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D009757:Nylons; D020349:Surface Plasmon Resonance
chemical_list: D009757:Nylons; D004247:DNA