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Search for the optimal linker in tandem hairpin polyamides

Kers, Inger and Dervan, Peter B. (2002) Search for the optimal linker in tandem hairpin polyamides. Bioorganic and Medicinal Chemistry, 10 (10). pp. 3339-3349. ISSN 0968-0896. doi:10.1016/S0968-0896(02)00221-3. https://resolver.caltech.edu/CaltechAUTHORS:20160510-081404661

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Abstract

In order to target specific DNA sequences ≥10 base pairs in size by minor groove binding ligands, a search for the optimal linker in dimers of hairpin polyamides was initiated. Two series of tandem polyamides ImPyIm-(R)[ImPyIm-(R)^(H2N)γ-PyPyPy-L]^(HN)γ-PyPyPy-β-Dp (1a–e), where L represents a series of 4–8 carbon long aliphatic amino acid linkers, and ImPyIm-(R)[ImPyIm-(R)^(H2N)γ-PyPyPyIm-L]^(HN)γ-PyPyPy-β-Dp (2a–e), where L represents a series of 2–6 carbon long aliphatic amino acid linkers, were synthesized and characterized by quantitative DNase I footprinting. β, γ and Dp represents β-alanine, γ-aminobutyric acid, and 3-(dimethylamino)propylamine, respectively. It was found that the five-carbon 5-aminovaleric acid (δ), is suitable to span one base-pair (bp) of DNA when incorporated into a tandem polyamide. ImPyIm-(R)[ImPyIm-(R)^(H2N)γ-PyPyPy-δ]^(HN)γ-PyPyPy-β-Dp (1b) binds the 10 bp binding-site 5′-AGTGAAGTGA-3′ with equilibrium association constant K_a=3.2×10^(10) M^(−1) and ImPyIm-(R)[ImPyIm-(R)^(H2N)γ-PyPyPyIm-δ]^(HN)γ-PyPyPy-β-Dp (2d) binds the 11 bp binding-site 5′-AGTGATAGTGA-3′ with K_a=9.7×10^9 M^(−1). Tandem 1b also bind the 11 bp site but with lower affinity affording a 15-fold specificity for the shorter binding site. Replacing a methylene group in the amino acid linker with an oxygen atom to form tandem polyamide ImPyIm-(R)[ImPyIm-(R)^(H2N)γ-PyPyPy-E]^(HN)γ-PyPyPy-β-Dp (4) where E represents the ether linker, resulted in that an 80-fold specificity for the 10 bp binding site over the 11 bp site.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/S0968-0896(02)00221-3DOIArticle
http://www.sciencedirect.com/science/article/pii/S0968089602002213PublisherArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2002 Elsevier Science Ltd. Received 11 February 2002; accepted 12 April 2002. We are grateful to the National Institutes of Health (GM 27681) for research support, and Swedish Research Council for Engineering Sciences (TFR) and The Swedish Foundation for International Cooperation in Research and Higher Education (STINT) for postdoctoral fellowships to I.K.
Funders:
Funding AgencyGrant Number
NIHGM-27681
Swedish Research Council for Engineering SciencesUNSPECIFIED
Swedish Foundation for International Cooperation in Research and Higher Education (STINT)UNSPECIFIED
Issue or Number:10
DOI:10.1016/S0968-0896(02)00221-3
Record Number:CaltechAUTHORS:20160510-081404661
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160510-081404661
Official Citation:Inger Kers, Peter B Dervan, Search for the Optimal Linker in Tandem Hairpin Polyamides, Bioorganic & Medicinal Chemistry, Volume 10, Issue 10, October 2002, Pages 3339-3349, ISSN 0968-0896, http://dx.doi.org/10.1016/S0968-0896(02)00221-3. (http://www.sciencedirect.com/science/article/pii/S0968089602002213)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66814
Collection:CaltechAUTHORS
Deposited By: Victoria Brennan
Deposited On:18 May 2016 18:53
Last Modified:11 Nov 2021 00:03

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