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Characterization and Solubilization of Pyrrole−Imidazole Polyamide Aggregates

Hargrove, Amanda E. and Raskatov, Jevgenij A. and Meier, Jordan L. and Montgomery, David C. and Dervan, Peter B. (2012) Characterization and Solubilization of Pyrrole−Imidazole Polyamide Aggregates. Journal of Medicinal Chemistry, 55 (11). pp. 5425-5432. ISSN 0022-2623. PMCID PMC3375050. doi:10.1021/jm300380a. https://resolver.caltech.edu/CaltechAUTHORS:20120716-095438604

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Abstract

To optimize the biological activity of pyrrole–imidazole polyamide DNA-binding molecules, we characterized the aggregation propensity of these compounds through dynamic light scattering and fractional solubility analysis. Nearly all studied polyamides were found to form measurable particles 50–500 nm in size under biologically relevant conditions, while HPLC-based analyses revealed solubility trends in both core sequences and peripheral substituents that did not correlate with overall ionic charge. The solubility of both hairpin and cyclic polyamides was increased upon addition of carbohydrate solubilizing agents, in particular, 2-hydroxypropyl-β-cyclodextrin (HpβCD). In mice, the use of HpβCD allowed for improved injection conditions and subsequent investigations of the availability of polyamides in mouse plasma to human cells. The results of these studies will influence the further design of Py-Im polyamides and facilitate their study in animal models.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/jm300380aDOIArticle
http://pubs.acs.org/doi/abs/10.1021/jm300380aPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375050/PubMed CentralArticle
http://pubs.acs.org/doi/suppl/10.1021/jm300380aPublisherSupporting Information
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2012 American Chemical Society. ACS AuthorChoice. Received: March 20, 2012. Publication Date (Web): May 18, 2012. We thank Dr. Jennifer Keefe (California Institute of Technology) and Sigrid Kuebler (Wyatt Technology Corporation) for assistance with DLS experimentation and data analysis and Dr. Adam Urbach (Trinity University) for helpful discussions. A.E.H. thanks the California Tobacco-Related Disease Research Program (19FT-0105) and the NIH (NRSA number 1F32CA156833) for postdoctoral support. J.A.R. is grateful to the Alexander von Humboldt foundation for the award of a Feodor Lynen postdoctoral fellowship. J.L.M. acknowledges the American Cancer Society for a postdoctoral fellowship (PF-10-015-01-CDD). D.C.M. thanks the National Institutes of Health for a Cellular, Biochemical, and Molecular Sciences Predoctoral Research training grant (5T32GM007616). This work was supported by the Ellison Medical Foundation (AG-SS-2256-09) and NIH grants (GM27681, GM51747). The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program19FT-0105
NIH Postdoctoral Fellowship1F32CA156833
Alexander von Humboldt FoundationUNSPECIFIED
American Cancer SocietyPF-10-015-01-CDD
NIH5T32GM007616
Ellison Medical FoundationAG-SS-2256-09
NIHGM-27681
NIHGM-51747
Issue or Number:11
PubMed Central ID:PMC3375050
DOI:10.1021/jm300380a
Record Number:CaltechAUTHORS:20120716-095438604
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120716-095438604
Official Citation:Characterization and Solubilization of Pyrrole–Imidazole Polyamide Aggregates Amanda E. Hargrove, Jevgenij A. Raskatov, Jordan L. Meier, David C. Montgomery, and Peter B. Dervan Journal of Medicinal Chemistry 2012 55 (11), 5425-5432 DOI: 10.1021/jm300380a
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:32460
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:16 Jul 2012 17:30
Last Modified:09 Nov 2021 21:27

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