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Alternative heterocycles for DNA recognition: an N-methylpyrazole/N-methylpyrrole pair specifies for A·T/T·A base pairs

Nguyen-Hackley, Doan H. and Szewczyk, Jason W. and Baird, Eldon E. and Dervan, Peter B. (2001) Alternative heterocycles for DNA recognition: an N-methylpyrazole/N-methylpyrrole pair specifies for A·T/T·A base pairs. Bioorganic and Medicinal Chemistry, 9 (1). pp. 7-17. ISSN 0968-0896. https://resolver.caltech.edu/CaltechAUTHORS:20160510-082735675

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Abstract

Side-by-side pairs of three five-membered rings, N-methylpyrrole (Py), N-methylimidazole (Im), and N-methylhydroxypyrrole (Hp), have been demonstrated to distinguish each of the four Watson–Crick base pairs in the minor groove of DNA. However, not all DNA sequences targeted by these pairing rules achieve affinities and specificities comparable to DNA binding proteins. We have initiated a search for new heterocycles which can expand the sequence repetoire currently available. Two heterocyclic aromatic amino acids, N-methylpyrazole (Pz) and 4-methylthiazole (Th), were incorporated into a single position of an eight-ring polyamide of sequence ImImXPy-γ-ImPyPyPy-β-Dp to examine the modulation of affinity and specificity for DNA binding by a Pz/Py pair and/or a Th/Py pair. The X/Py pairings Pz/Py and Th/Py were evaluated by quantitative DNase I footprint titrations on a DNA fragment with the four sites 5′-TGGNCA-3′ (N=T, A, G, C). The Pz/Py pair binds T·A and A·T with similar affinity to a Py/Py pair but with improved specificity, disfavoring both G·C and C·G by about 100-fold. The Th/Py pair binds poorly to all four Watson–Crick base pairs. These results demonstrate that in some instances new heterocyclic aromatic amino acid pairs can be incorporated into imidazole–pyrrole polyamides to mimic the DNA specificity of Py/Py pairs which may be relevant as biological criteria in animal studies become important.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S0968-0896(00)00219-4DOIArticle
http://www.sciencedirect.com/science/article/pii/S0968089600002194PublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2000 Elsevier Science Ltd. Received 26 April 2000; accepted 13 July 2000. We are grateful to the National Institutes of Health (GM 27681) for research support, National Institutes of Health for a research service award to J.W.S., The Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. and the Natural Sciences and Engineering Research Council of Canada for a post-graduate scholarship to D.H.N.
Funders:
Funding AgencyGrant Number
NIHGM-27681
NIH Predoctoral FellowshipUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Natural Sciences and Engineering Research Council of Canada (NSERC)UNSPECIFIED
Issue or Number:1
Record Number:CaltechAUTHORS:20160510-082735675
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160510-082735675
Official Citation:Doan H. Nguyen, Jason W. Szewczyk, Eldon E. Baird, Peter B. Dervan, Alternative heterocycles for DNA recognition: an N-methylpyrazole/N-methylpyrrole pair specifies for AT/TA base pairs, Bioorganic & Medicinal Chemistry, Volume 9, Issue 1, January 2001, Pages 7-17, ISSN 0968-0896, http://dx.doi.org/10.1016/S0968-0896(00)00219-4. (http://www.sciencedirect.com/science/article/pii/S0968089600002194)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66828
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 18:57
Last Modified:26 Nov 2019 11:15

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