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Targeting DNA Mismatches with Rhodium Intercalators Functionalized with a Cell-Penetrating Peptide

Brunner, Jens and Barton, Jacqueline K. (2006) Targeting DNA Mismatches with Rhodium Intercalators Functionalized with a Cell-Penetrating Peptide. Biochemistry, 45 (40). pp. 12295-12302. ISSN 0006-2960. https://resolver.caltech.edu/CaltechAUTHORS:20160229-103206591

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Abstract

Cell-penetrating peptides are widely used to deliver cargo molecules into cells. Here we describe the synthesis, characterization, DNA binding, and cellular uptake studies of a series of metal−peptide conjugates containing oligoarginine as a cell-penetrating peptide. d-Octaarginine units are appended onto a rhodium intercalator containing the sterically expansive chrysenequinone diimine (chrysi) ligand to form Rh(chrysi)(phen)(bpy)^(3+)-tethered oligoarginine conjugates, where the peptide is attached to the ancillary bpy ligand; some conjugates also include a fluorescein or thiazole orange tag. These complexes bind and with photoactivation selectively cleave DNA neighboring single-base mismatches. The presence of the oligoarginines is found to increase the nonspecific binding affinity of the complexes for both matched and mismatched DNA, but for these conjugates, photocleavage remains selective for the mismatched site, as assayed using both gel electrophoresis and mass spectrometry experiments. Significantly, the rhodium complex does not interfere with the delivery properties of the cell-penetrating peptide. Confocal microscopy experiments show rapid nuclear localization of the metal−peptide conjugates containing the tethered fluorescein. Mass spectrometry experiments confirm the association of the rhodium with the HeLa cells. These results provide a strategy for targeting mismatch-selective metal complexes inside cell nuclei.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi061198oDOIArticle
http://pubs.acs.org/doi/abs/10.1021/bi061198oPublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/bi061198oPublisherSupporting Information
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2006 American Chemical Society. Received June 15, 2006; Revised Manuscript Received August 10, 2006. Publication Date (Web): September 19, 2006. Financial support for this work from the National Institutes of Health (Grant GM33309 to J.K.B.) and a postdoctoral fellowship of the German Academic Exchange Service (to J.B.) are acknowledged.
Funders:
Funding AgencyGrant Number
NIHGM33309
Deutscher Akademischer Austauschdienst (DAAD)UNSPECIFIED
Issue or Number:40
Record Number:CaltechAUTHORS:20160229-103206591
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160229-103206591
Official Citation:Targeting DNA Mismatches with Rhodium Intercalators Functionalized with a Cell-Penetrating Peptide Jens Brunner and Jacqueline K. Barton Biochemistry 2006 45 (40), 12295-12302 DOI: 10.1021/bi061198o
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64845
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:29 Feb 2016 19:32
Last Modified:03 Oct 2019 09:41

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