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Expanding the recognition of the minor groove of DNA by incorporation of β-alanine in hairpin polyamides

Wang, Clay C. C. and Ellervik, Ulf and Dervan, Peter B. (2001) Expanding the recognition of the minor groove of DNA by incorporation of β-alanine in hairpin polyamides. Bioorganic and Medicinal Chemistry, 9 (3). pp. 653-657. ISSN 0968-0896. doi:10.1016/S0968-0896(00)00282-0.

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In order to expand the recognition code by hairpin polyamides to include DNA sequences of the type 5′-CWWC-3′ two polyamides, PyPyPyPy-(R)^(H_2^N)γ-ImPyPyIm-β-Dp (1) and PyPyPyPy-(R)^(H_2^N)γ-ImPy-β-Im-β-Dp (2) were synthesized which have in common an Py/Im pair in the terminal position for targeting C·G but differ with respect to internal placement of a β-alanine residue. The equilibrium association constants (K_a) were determined at four DNA sites which differ at a single common position, 5′-TNTACA-3′ (N=T, A, G, C). Quantitative DNase I footprint titration experiments reveal that the eight-ring hairpin PyPyPyPy-(R)^(H_2^N)γ-ImPyPyIm-β-Dp (1) binds the four binding sites with similar affinities, K_a=1.3–1.9×10^(10) M^(−1) indicating that there is no preference for the position N. In contrast, a redesigned polyamide PyPyPyPy-(R)^(H_2^N)γ-ImPy-β-Im-β-Dp (2) that places an internal flexible aliphatic β-alanine to the 5′-side of a key imidazole group bound the match site 5′-TCTACA-3′ with high affinity and good sequence discrimination (K_a(match)=4.9×10^(10) M^(−1) and the single base pair mismatch sites with 5- to 25-fold lower affinity). These results expand the repertoire of sequences targetable by hairpins and emphasize the importance of β-alanine as a key element for minor groove recognition.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2001 Elsevier Science Ltd. Received 9 August 2000; accepted 16 October 2000. We are grateful to the National Institutes of Health (GM-27681) for research support, the Knut and Alice Wallenberg Foundation for a post-doctoral fellowship to U.E. and the National Institutes of Health for a research traineeship award (GM 08501) to C.C.C.W. We thank G. M. Hathaway for MALDI-TOF mass spectrometry.
Funding AgencyGrant Number
Knut and Alice Wallenberg FoundationUNSPECIFIED
NIH Predoctoral FellowshipGM-08501
Issue or Number:3
Record Number:CaltechAUTHORS:20160510-082733090
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Official Citation:Clay C.C. Wang, Ulf Ellervik, Peter B. Dervan, Expanding the recognition of the minor groove of DNA by incorporation of β-alanine in hairpin polyamides, Bioorganic & Medicinal Chemistry, Volume 9, Issue 3, March 2001, Pages 653-657, ISSN 0968-0896, (
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66827
Deposited By: Victoria Brennan
Deposited On:18 May 2016 19:14
Last Modified:11 Nov 2021 00:03

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