Affinity And Kinetic Modulation Of Polyamide–DNA Interactions By N-modification Of The Heterocycles

Document Type

Article

Publication Date

8-2013

Publication Source

Biopolymers

Volume Number

99

Issue Number

8

First Page

497

Last Page

507

Publisher

Wiley-Blackwell

ISSN

0006-3525

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, TM, 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 x 108 M1 and Keq = 6.2 x 107 M1, 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. (c) 2013 Wiley Periodicals, Inc. Biopolymers 99: 497507, 2013.

Keywords

polyamides; diamino; dicationic; gene control; ACGCGT; MCB; Mlu1; cell-cycle box; pyrrole; imidazole; DNA; minor groove binder; sequence selectivity; binding affinity; kinetics KeyWords Plus: PYRROLE-IMIDAZOLE POLYAMIDES; MINOR-GROOVE BINDERS; CELL-CYCLE BOX; MOLECULAR RECOGNITION; SEQUENCE RECOGNITION; DNA; DISTAMYCIN; BINDING; NMR

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