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Characterization and Solubilization of Pyrrole–Imidazole Polyamide Aggregates

Authors
Journal
Journal of Medicinal Chemistry
0022-2623
Publisher
American Chemical Society
Publication Date
Volume
55
Issue
11
Identifiers
DOI: 10.1021/jm300380a
Keywords
  • Article
Disciplines
  • Biology
  • Design

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.

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