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Cycle polyamide motif for recognition of the minor groove of DNA

Herman, David M. and Turner, James M. and Baird, Eldon E. and Dervan, Peter B. (1999) Cycle polyamide motif for recognition of the minor groove of DNA. Journal of the American Chemical Society, 121 (6). pp. 1121-1129. ISSN 0002-7863. doi:10.1021/ja983206x.

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Motifs for covalent linkage of side-by-side complexes of pyrrole−imidazole (Py−Im) polyamides in the DNA minor groove provide for small molecules that specifically recognize predetermined sequences with subnanomolar affinity. Polyamide subunits linked by a turn-specific γ-aminobutyric acid (γ) residue form hairpin polyamide structures. Selective amino-substitution of the prochiral α-position of the γ-turn residue relocates the cationic charge from the hairpin C terminus. Here we report the synthesis of pyrrole resin as well as a solid-phase strategy for the preparation of cycle polyamides. The DNA binding properties of two eight-ring cycle polyamides were analyzed on a DNA restriction fragment containing six base pair match and mismatch binding sites. Quantitative footprint titrations demonstrate that a cycle polyamide of sequence composition cyclo-(γ-ImPyPyPy-(R)^(H2N)γ-ImPyPyPy-) binds a 5‘-AGTACT-3‘ site with an equilibrium association constant K_a = 7.6 × 10^(10) M^(-1), a 3600-fold enhancement relative to the unlinked homodimer (ImPyPyPy-β-Dp)_2·5‘-AGTACT-3‘, and an 8-fold enhancement relative to hairpin analogue ImPyPyPy-(R)^(H2N)γ-ImPyPyPy-C3−OH·5‘-AGTACT-3‘. Replacement of a single nitrogen atom with a C−H (Im→Py) regulates affinity and specificity of the cycle polyamide by 2 orders of magnitude. The results presented here suggest that addition of a chiral γ-turn combined with placement of a second γ-turn within the hairpin structure provides a cycle polyamide motif with favorable DNA binding properties.

Item Type:Article
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URLURL TypeDescription Information
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1999 American Chemical Society. Received September 8, 1998. Publication Date (Web): January 27, 1999. We are grateful to the National Institutes of Health (GM-27681) for research support, the National Institutes of Health for a research service award to D.M.H., J. Edward Richter for an undergraduate fellowship to J.M.T., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. We thank G.M. Hathaway for MALDI-TOF mass spectrometry.
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
J. Edward RichterUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:6
Record Number:CaltechAUTHORS:20160510-092504987
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Official Citation:Cycle Polyamide Motif for Recognition of the Minor Groove of DNA David M. Herman, James M. Turner, Eldon E. Baird, and Peter B. Dervan Journal of the American Chemical Society 1999 121 (6), 1121-1129 DOI: 10.1021/ja983206x
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66855
Deposited By: Victoria Brennan
Deposited On:10 May 2016 18:59
Last Modified:11 Nov 2021 00:23

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