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Importance of sequence specific hydrophobicity in synthetic protein transduction domain mimics.

Authors
  • Sgolastra, Federica
  • Minter, Lisa M
  • Osborne, Barbara A
  • Tew, Gregory N
Type
Published Article
Journal
Biomacromolecules
Publisher
American Chemical Society
Publication Date
Mar 10, 2014
Volume
15
Issue
3
Pages
812–820
Identifiers
DOI: 10.1021/bm401634r
PMID: 24506414
Source
Medline
License
Unknown

Abstract

A new series of synthetic protein transduction domain mimics (PTDMs) was designed to analyze the importance of guanidine and phenyl group segregation along the backbone on their membrane interaction and cellular internalization abilities. ROMP was utilized to synthesize three polymers: nonsegregated homopolymers, intermediately segregated gradient copolymers, and strongly segregated block copolymers. In order to understand the role of functional group segregation on activity, it was important to design monomers that enabled these three different polymer topologies, or constitutional macromolecular isomers, to be prepared with identical chemical compositions. The structure-activity relationships were evaluated by both a biophysical assay, using dye-loaded vesicles, and by in vitro cellular uptake studies of fluorescently labeled chains. The results showed that functional group segregation impacts activity. In general, the nonsegregated homopolymer was the most active in both assays but also showed larger, ill-defined aggregates compared to either the gradient or block copolymers. It was also the most cytotoxic of the three isomers. As a result, the gradient copolymer with intermediate segregation optimizes activity and solubility with low cytotoxicity. This study gives new design guidelines for the development of PTDMs.

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