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Sequence specific alkylation of DNA by hairpin pyrrole-imidazole polyamide conjugates

Wurtz, Nicholas R. and Dervan, Peter B. (2000) Sequence specific alkylation of DNA by hairpin pyrrole-imidazole polyamide conjugates. Chemistry and Biology, 7 (3). pp. 153-161. ISSN 1074-5521. http://resolver.caltech.edu/CaltechAUTHORS:20160510-091112555

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Abstract

Background: Pyrrole–imidazole polyamides are synthetic ligands that recognize predetermined sequences in the minor groove of DNA with affinities and specificities comparable to those of DNA-binding proteins. As a result of their DNA-binding properties, polyamides could deliver reactive moieties for covalent reaction at specific DNA sequences and thereby inhibit DNA–protein interactions. Site-specific alkylation of DNA could be a useful tool for regulating gene expression. As a minimal first step, we set out to design and synthesize a class of hairpin polyamides equipped with DNA alkylating agents and characterize the specificity and yield of covalent modification. Results: Bis(dichloroethylamino)benzene derivatives of the well-characterized chlorambucil (CHL) were attached to the γ turn of an eight-ring hairpin polyamide targeted to the HIV-1 promoter. We found that a hairpin polyamide–CHL conjugate binds and selectively alkylates predetermined sites in the HIV promoter at subnanomolar concentrations. Cleavage sites were determined on both strands of a restriction fragment containing the HIV-1 promoter, revealing good specificity and a high yield of alkylation. Conclusions: The ability of polyamide–CHL conjugates to sequence specifically alkylate double-stranded DNA in high yield and at low concentrations sets the stage for testing their use as regulators of gene expression in cell culture and ultimately in complex organisms.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S1074-5521(00)00085-5DOIArticle
http://www.sciencedirect.com/science/article/pii/S1074552100000855PublisherArticle
Additional Information:© 2000 Elsevier Science Ltd. Received: 14 December 1999; Accepted: 6 January 2000; Published: 14 February 2000. We are grateful to the National Institutes of Health General Medical Sciences for research support, and to the Ralph M Parsons Foundation for a predoctoral fellowship to N.R.W.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Subject Keywords:Alkylation; DNA; Minor groove; Molecular recognition
Record Number:CaltechAUTHORS:20160510-091112555
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20160510-091112555
Official Citation:Nicholas R Wurtz, Peter B Dervan, Sequence specific alkylation of DNA by hairpin pyrrole–imidazole polyamide conjugates, Chemistry & Biology, Volume 7, Issue 3, 1 March 2000, Pages 153-161, ISSN 1074-5521, http://dx.doi.org/10.1016/S1074-5521(00)00085-5. (http://www.sciencedirect.com/science/article/pii/S1074552100000855)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66850
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:02
Last Modified:18 May 2016 21:02

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