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Published August 2001 | public
Journal Article

Inhibition of major groove DNA binding bZIP proteins by positive patch polyamides

Abstract

Cell permeable synthetic ligands that bind to predetermined DNA sequences offer a chemical approach to gene regulation, provided inhibition of a broad range of DNA transcription factors can be achieved. DNA minor groove binding polyamides containing aminoalkyl substituents at the N-1 of a single pyrrole residue display inhibitory effects for a bZIP protein which binds exclusively in the DNA major groove. For major groove protein inhibition, specific protein-DNA contacts along the phosphate backbone were targeted with the positively charged dimethylamino substituent on the backbone of a minor groove binding polyamide hairpin. Remarkably, these polyamides bind DNA with enhanced affinity and uncompromised specificity when compared to polyamides with the aminoalkyl moiety at the C-terminus. By adding bZIP transcription factors to the class of protein-DNA complexes that can be disrupted by minor groove binding ligands, these results may increase the functional utility of polyamides as regulators of gene expression.

Additional Information

© 2001 Elsevier Science Ltd. Received 30 January 2001; accepted 4 April 2001. The authors are grateful to the National Institutes of Health for research support, the National Science Foundation for a predoctoral fellowship to R.E.B., Bristol-Myers Squibb and the Ralph M. Parson Foundation for predoctoral fellowships to R.E.B. and N.R.W., and the National Institutes of Health for a research service award to J.W.S. We thank G.M. Hathaway and the Caltech Protein/Peptide Microanalytical Laboratory for MALDI-TOF mass spectrometry.

Additional details

Created:
August 19, 2023
Modified:
October 18, 2023