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Influence of structural variation on nuclear localization of DNA-binding polyamide-fluorophore conjugates

Edelson, Benjamin S. and Best, Timothy P. and Olenyuk, Bogdan and Nickols, Nicholas G. and Doss, Raymond M. and Foister, Shane and Heckel, Alexander and Dervan, Peter B. (2004) Influence of structural variation on nuclear localization of DNA-binding polyamide-fluorophore conjugates. Nucleic Acids Research, 32 (9). pp. 2802-2818. ISSN 0305-1048. PMCID PMC419610.

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A pivotal step forward in chemical approaches to controlling gene expression is the development of sequence-specific DNA-binding molecules that can enter live cells and traffic to nuclei unaided. DNA-binding polyamides are a class of programmable, sequence-specific small molecules that have been shown to influence a wide variety of protein–DNA interactions. We have synthesized over 100 polyamide-fluorophore conjugates and assayed their nuclear uptake profiles in 13 mammalian cell lines. The compiled dataset, comprising 1300 entries, establishes a benchmark for the nuclear localization of polyamide-dye conjugates. Compounds in this series were chosen to provide systematic variation in several structural variables, including dye composition and placement, molecular weight, charge, ordering of the aromatic and aliphatic amino-acid building blocks and overall shape. Nuclear uptake does not appear to be correlated with polyamide molecular weight or with the number of imidazole residues, although the positions of imidazole residues affect nuclear access properties significantly. Generally negative determinants for nuclear access include the presence of a ß-Ala-tail residue and the lack of a cationic alkyl amine moiety, whereas the presence of an acetylated 2,4-diaminobutyric acid-turn is a positive factor for nuclear localization. We discuss implications of these data on the design of polyamide-dye conjugates for use in biological systems.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2004 Oxford University Press Received March 19, 2004; Revised and Accepted April 22, 2004; Published online 20 May 2004 The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. This article is dedicated to the memory of Prof. Claude Helene. Supplementary Material is available at NAR Online. We are grateful to the National Institutes of Health for support (Grant GM57148) and for predoctoral support to T.P.B. and R.M.D. (Grant T32-GM08501), to the Howard Hughes Medical Institute for a fellowship to B.S.E., and to the National Science Foundation for a predoctoral fellowship to S.F.. Mass spectral analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering of Caltech, supported in part by National Science Foundation Materials Research Science and Engineering program.
Funding AgencyGrant Number
NIH Predoctoral FellowshipT32-GM08501
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NSF Predoctoral FellowshipUNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC419610
Record Number:CaltechAUTHORS:EDEnar04
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Official Citation:Benjamin S. Edelson, Timothy P. Best, Bogdan Olenyuk, Nicholas G. Nickols, Raymond M. Doss, Shane Foister, Alexander Heckel, and Peter B. Dervan Influence of structural variation on nuclear localization of DNA‐binding polyamide‐fluorophore conjugates Nucl. Acids Res. (2004) 32 (9): 2802-2818 doi:10.1093/nar/gkh609
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:772
Deposited By: Archive Administrator
Deposited On:29 Sep 2005
Last Modified:26 Nov 2019 11:15

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