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Affinity and kinetic modulation of polyamide–DNA interactions by N ‐modification of the heterocycles
Author(s) -
Ramos Joseph P.,
Babu Balaji,
Chavda Sameer,
Liu Yang,
Plaunt Adam,
Ferguson Amanda,
Savagian Mia,
Lee Megan,
Tzou Samuel,
Lin Shicai,
Kiakos Konstantinos,
Wang Shuo,
Lee Moses,
Hartley John A.,
Wilson W. David
Publication year - 2013
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.22205
Subject(s) - chemistry , dna , footprinting , molecule , selectivity , stereochemistry , minor groove , sequence (biology) , polyamide , combinatorial chemistry , biophysics , biochemistry , base sequence , organic chemistry , biology , catalysis
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, ΔT M , 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, K eq = 2.8 × 10 8 M −1 and K eq = 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. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 497–507, 2013.