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Enhancing the cellular uptake of Py–Im polyamides through next-generation aryl turns

Meier, Jordan L. and Montgomery, David C. and Dervan, Peter B. (2012) Enhancing the cellular uptake of Py–Im polyamides through next-generation aryl turns. Nucleic Acids Research, 40 (5). pp. 2345-2356. ISSN 0305-1048. PMCID PMC3300022. doi:10.1093/nar/gkr970. https://resolver.caltech.edu/CaltechAUTHORS:20120420-144717132

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Abstract

Pyrrole–imidazole (Py–Im) hairpin polyamides are a class of programmable, sequence-specific DNA binding oligomers capable of disrupting protein–DNA interactions and modulating gene expression in living cells. Methods to control the cellular uptake and nuclear localization of these compounds are essential to their application as molecular probes or therapeutic agents. Here, we explore modifications of the hairpin γ-aminobutyric acid turn unit as a means to enhance cellular uptake and biological activity. Remarkably, introduction of a simple aryl group at the turn potentiates the biological effects of a polyamide targeting the sequence 5′-WGWWCW-3′ (W = A/T) by up to two orders of magnitude. Confocal microscopy and quantitative flow cytometry analysis suggest this enhanced potency is due to increased nuclear uptake. Finally, we explore the generality of this approach and find that aryl-turn modifications enhance the uptake of all polyamides tested, while having a variable effect on the upper limit of polyamide nuclear accumulation. Overall this provides a step forward for controlling the intracellular concentration of Py–Im polyamides that will prove valuable for future applications in which biological potency is essential.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/nar/gkr970DOIArticle
http://nar.oxfordjournals.org/content/40/5/2345PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3300022//PubMed CentralArticle
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2011 The Author(s). Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received September 8, 2011. Revision received October 13, 2011. Accepted October 14, 2011. First published online: November 12, 2011. Mass spectrometry analyses were performed in the Mass Spectrometry Laboratory of the Division of Chemistry and Chemical Engineering at the California Institute of Technology. Flow cytometry analyses were performed at the Caltech Flow Cytometry Cell Sorting Facility. We thank Rochelle Diamond for support and technical expertise in performing flow cytometry experiments, and William Dempsey for helpful discussions regarding confocal microscopy. FUNDING: National Institutes of Health (grant numbers GM51747 and GM27681); American Cancer Society (grant number PF-10-015-01-CDD to J.L.M, postdoctoral fellowship) and National Institutes of Health Cellular, Biochemical, and Molecular Sciences Predoctoral Research training grant (grant number 5T32GM007616 to D.C.M.). Funding for open access charge: National Institutes of Health (grant numbers GM51747). Conflict of interest statement. None declared.
Funders:
Funding AgencyGrant Number
NIHGM-51747
NIHGM-27681
American Cancer SocietyPF-10-015-01-CDD
NIH Postdoctoral Fellowship5T32GM007616
Issue or Number:5
PubMed Central ID:PMC3300022
DOI:10.1093/nar/gkr970
Record Number:CaltechAUTHORS:20120420-144717132
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120420-144717132
Official Citation:Jordan L. Meier, David C. Montgomery, and Peter B. Dervan Enhancing the cellular uptake of Py–Im polyamides through next-generation aryl turns Nucl. Acids Res. (2012) 40 (5): 2345-2356 first published online November 12, 2011 doi:10.1093/nar/gkr970
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:30241
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:23 Apr 2012 15:31
Last Modified:09 Nov 2021 19:43

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