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Regulation of gene expression with pyrrole-imidazole polyamides

Dervan, Peter B. and Fechter, Eric J. and Edelson, Benjamin S. and Gottesfeld, Joel M. (2004) Regulation of gene expression with pyrrole-imidazole polyamides. In: Pseudo-Peptides in Drug Development. Wiley-VCH , Weinheim, pp. 121-152. ISBN 9783527306336. https://resolver.caltech.edu/CaltechAUTHORS:20160519-124154093

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Abstract

The natural product distamycin contains three N-methylpyrrole amino acids and binds in the minor groove of DNA at A,T tracts 4-5 base pairs (bp) in size. Distamycin inhibits DNA-dependent processes, including transcription, and has antibacterial, antimalarial, antifungal and antiviral activities, but is of limited use because of toxicity. Efforts to bring distamycin analogs to the clinic have focused on anti-infective therapeutics. These compounds have been optimized for pathogen activity and pharmacological properties, with DNA binding specificity not providing a major driving force in ligand selection. Dickerson, Rich and Wemmer revealed by X-ray and NMR structural studies that the crescent-shaped molecule could bind A,T tracts in both 1:1 and 2:1 ligand:DNA stoichiometries. Informed by these structures, we explored whether designed distamycin analogs could be tuned by chemical modification in a predictable fashion to bind to a very large number of different DNA sequences, i.e. create an artificial small molecule language to read the minor groove digitally, similar in function to nature's proteins. This might underpin a rational chemical approach to the regulation of gene expression by chemical methods. After a 20 year search, we demonstrated that synthetic analogs pf the N-methylpyrrole (Py) carboxamide ring afford a set of heterocycles that can be combined -- as unsymmetrical ring pairs -- in a modular fashion to recognize specifically a large repertoire of DNA sequences with affinities and specificities comparable to DNA-binding proteins. In this chapter we describe advances in the field of DNA-binding polyamides, cellular and nuclear uptake properties and recent biological applications.


Item Type:Book Section
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1002/3527601902.ch3DOIArticle
http://onlinelibrary.wiley.com/doi/10.1002/3527601902.ch3/summaryPublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 Wiley-VCH. We are grateful to the National Institutes of Health for research support. E. J. F. is supported by an NIH Research Service Award and a Ralph M. Parsons Fellowship. B. S. E. is supported by a pre-doctoral fellowship from the Howard Hughes Medical Institute.
Funders:
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:gene expression; regulation; inhibition; pyrrole-imidazole polyamides; pairing rules; hairpin motif; cycle motif; binding site size; β-alanine; solid phase methods; gene activation; nucleosomes; nuclear uptake; DNA detection
DOI:10.1002/3527601902.ch3
Record Number:CaltechAUTHORS:20160519-124154093
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160519-124154093
Official Citation:Dervan, P. B., Fechter, E. J., Edelson, B. S. and Gottesfeld, J. M. (2004) Regulation of Gene Expression with Pyrrole-Imidazole Polyamides, in Pseudo-Peptides in Drug Development (ed P. E. Nielsen), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG. doi: 10.1002/3527601902.ch3
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67186
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:20 May 2016 00:03
Last Modified:11 Nov 2021 00:28

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