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Recognition of the DNA minor groove by pyrrole-imidazole polyamides: comparison of desmethyl- and N-methylpyrrole

Bremer, Ryan E. and Szewczyk, Jason W. and Baird, Eldon E. and Dervan, Peter B. (2000) Recognition of the DNA minor groove by pyrrole-imidazole polyamides: comparison of desmethyl- and N-methylpyrrole. Bioorganic and Medicinal Chemistry, 8 (8). pp. 1947-1955. ISSN 0968-0896. doi:10.1016/S0968-0896(00)00145-0.

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Polyamides consisting of N-methylpyrrole (Py), N-methylimidazole (Im), and N-methyl-3-hydroxypyrrole (Hp) are synthetic ligands that recognize predetermined DNA sequences with affinities and specificities comparable to many DNA-binding proteins. As derivatives of the natural products distamycin and netropsin, Py/Im/Hp polyamides have retained the N-methyl substituent, although structural studies of polyamide:DNA complexes have not revealed an obvious function for the N-methyl. In order to assess the role of the N-methyl moiety in polyamide:DNA recognition, a new monomer, desmethylpyrrole (Ds), where the N-methyl moiety has been replaced with hydrogen, was incorporated into an eight-ring hairpin polyamide by solid-phase synthesis. MPE footprinting, affinity cleavage, and quantitative DNase I footprinting revealed that replacement of each Py residue with Ds resulted in identical binding site size and orientation and similar binding affinity for the six-base-pair (bp) target DNA sequence. Remarkably, the Ds-containing polyamide exhibited an 8-fold loss in specificity for the match site versus a mismatched DNA site, relative to the all-Py parent. Polyamides with Ds exhibit increased water solubility, which may alter the cell membrane permeability properties of the polyamide. The addition of Ds to the repertoire of available monomers may prove useful as polyamides are applied to gene regulation in vivo. However, the benefits of Ds incorporation must be balanced with a potential loss in specificity.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2000 Elsevier Science Ltd. Received 14 February 2000; accepted 18 April 2000. We are grateful to the National Institutes of Health for research support, the National Science Foundation, Bristol-Myers Squibb and the Ralph M. Parsons Foundation for predoctoral fellowships to R.E.B., the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B., and the National Institutes of Health for a research service award to J.W.S.
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Bristol-Myers SquibbUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:8
Record Number:CaltechAUTHORS:20160510-091110474
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Official Citation:Ryan E Bremer, Jason W Szewczyk, Eldon E Baird, Peter B Dervan, Recognition of the DNA minor groove by pyrrole-imidazole polyamides: comparison of desmethyl- and N-methylpyrrole, Bioorganic & Medicinal Chemistry, Volume 8, Issue 8, August 2000, Pages 1947-1955, ISSN 0968-0896, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66848
Deposited By: Victoria Brennan
Deposited On:18 May 2016 20:43
Last Modified:11 Nov 2021 00:22

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