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Molecular Pharmacology

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Research ArticleArticle

Coupling to Polymeric Scaffolds Stabilizes Biofunctional Peptides for Intracellular Applications

Ivo R. Ruttekolk, Alokta Chakrabarti, Martin Richter, Falk Duchardt, Heike Glauner, Wouter P. R. Verdurmen, Jörg Rademann and Roland Brock
Molecular Pharmacology April 2011, 79 (4) 692-700; DOI: https://doi.org/10.1124/mol.110.068296
Ivo R. Ruttekolk
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Alokta Chakrabarti
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Martin Richter
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Falk Duchardt
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Heike Glauner
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Wouter P. R. Verdurmen
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Jörg Rademann
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Roland Brock
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Abstract

Here, we demonstrate that coupling to N-hydroxypropyl methacrylamide (HPMA) copolymer greatly enhances the activity of apoptosis-inducing peptides inside cells. Peptides corresponding to the BH3 domain of Bid were coupled to a thioester-activated HPMA (28.5 kDa) via native chemical ligation in a simple one-pot synthesis. Peptides and polymer conjugates were introduced into cells either by electroporation or by conjugation to the cell-penetrating peptide nona-arginine. The molecular basis of the increased activity is elucidated in detail. Loading efficiency and intracellular residence time were assessed by confocal microscopy. Fluorescence correlation spectroscopy was used as a separation-free analytical technique to determine proteolytic degradation in crude cell lysates. HPMA conjugation strongly increased the half-life of the peptides in crude cell lysates and inside cells, revealing proteolytic protection as the basis for higher activity.

Footnotes

  • This work was supported by the Volkswagen Foundation [Grant I/77 472]; and the Deutsche Forschungsgemeinschaft [Grants BR2443/5-1, Graduiertenkolleg 794, RA895/4-1, SFP765, project B4].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.068296.

  • ABBREVIATIONS:

    HPMA
    N-hydroxypropyl methacrylamide
    CPP
    cell-penetrating peptide
    DMSO
    dimethyl sulfoxide
    FCS
    fluorescence correlation spectroscopy
    PBS
    phosphate-buffered saline
    N.A.
    numerical aperture.

  • Received August 19, 2010.
  • Accepted December 30, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Coupling to Polymeric Scaffolds Stabilizes Biofunctional Peptides for Intracellular Applications

Ivo R. Ruttekolk, Alokta Chakrabarti, Martin Richter, Falk Duchardt, Heike Glauner, Wouter P. R. Verdurmen, Jörg Rademann and Roland Brock
Molecular Pharmacology April 1, 2011, 79 (4) 692-700; DOI: https://doi.org/10.1124/mol.110.068296

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Research ArticleArticle

Coupling to Polymeric Scaffolds Stabilizes Biofunctional Peptides for Intracellular Applications

Ivo R. Ruttekolk, Alokta Chakrabarti, Martin Richter, Falk Duchardt, Heike Glauner, Wouter P. R. Verdurmen, Jörg Rademann and Roland Brock
Molecular Pharmacology April 1, 2011, 79 (4) 692-700; DOI: https://doi.org/10.1124/mol.110.068296
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