Self-assembly of Filamentous Cell Penetrating Peptides for Gene Delivery

Part of the Methods in Molecular Biology book series (MIMB, volume 1777)


Cell penetrating peptides (CPPs) have been proven to be an effective vector to deliver a variety of membrane-impermeable macromolecules, such as DNAs, siRNAs, and proteins. Conventional single-chain CPPs typically suffer from severe protease degradation and fast clearance rate for in vivo therapeutic delivery application. In this chapter, we show that supramolecular assembly of de novo designed cationic multidomain peptides (MDPs) leads to nanostructured filaments with increased proteolytic stability and potent membrane activity necessary for improved transfection efficiency.

Key words

Self-assembly Cell penetrating peptide Gene delivery Membrane activity 



Clarkson University is acknowledged for the support of this work. We thank the Clarkson-Trudeau Partnership for providing seed fund to support this project. This study was supported by the National Science Foundation (DMR 1654426).


  1. 1.
    Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193CrossRefGoogle Scholar
  2. 2.
    Green M, Ishino M, Loewenstein PM (1989) Mutational analysis of HIV-1 Tat minimal domain peptides: identification of trans-dominant mutants that suppress HIV-LTR-driven gene expression. Cell 58:215–223CrossRefGoogle Scholar
  3. 3.
    Vives E, Brodin P, Lebleu B (1997) A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem 272:16010–16017CrossRefGoogle Scholar
  4. 4.
    Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY (2004) Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A 101:17867–17872CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fosgerau K, Hoffmann T (2015) Peptide therapeutics: current status and future directions. Drug Discov Today 20:122–128CrossRefPubMedGoogle Scholar
  6. 6.
    Dong H, Paramonov SE, Aulisa L, Bakota EL, Hartgerink JD (2007) Self-assembly of multidomain peptides: balancing molecular frustration controls conformation and nanostructure. J Am Chem Soc 129:12468–12472CrossRefPubMedGoogle Scholar
  7. 7.
    Som A, Tezgel AO, Gabriel GJ, Tew GN (2011) Self-activation in de novo designed mimics of cell-penetrating peptides. Angew Chem Int Ed 50:6147–6150CrossRefGoogle Scholar
  8. 8.
    Som A, Reuter A, Tew GN (2012) Protein transduction domain mimics: the role of aromatic functionality. Angew Chem Int Ed 51:980–983CrossRefGoogle Scholar
  9. 9.
    Lu H, Wang J, Bai Y, Lang JW, Liu S, Lin Y, Cheng J (2011) Ionic polypeptides with unusual helical stability. Nat Commun 2:206CrossRefPubMedGoogle Scholar
  10. 10.
    Yin L, Song Z, Kim KH, Zheng N, Tang H, Lu H, Gabrielson N, Cheng J (2013) Reconfiguring the architectures of cationic helical polypeptides to control non-viral gene delivery. Biomaterials 34:2340–2349CrossRefPubMedGoogle Scholar
  11. 11.
    Xu D, Jiang L, Singh A, Dustin D, Yang M, Liu L, Lund R, Sellati TJ, Dong H (2015) Designed supramolecular filamentous peptides: balance of nanostructure, cytotoxicity and antimicrobial activity. Chem Commun 51:1289–1292CrossRefGoogle Scholar
  12. 12.
    Xu D, Dustin D, Jiang L, Samways DSK, Dong H (2015) Designed filamentous cell penetrating peptides: probing supramolecular structure-dependent membrane activity and transfection efficiency. Chem Commun 51:11757–11760CrossRefGoogle Scholar
  13. 13.
    Yang M, Xu D, Jiang L, Zhang L, Dustin D, Lund R, Liu L, Dong H (2014) Filamentous supramolecular peptide-drug conjugates as highly efficient drug delivery vehicles. Chem Commun 50:4827–4830CrossRefGoogle Scholar
  14. 14.
    Bukhari M, Deng H, Jones N, Towne Z, Woodworth CD, Samways DSK (2015) Selective permeabilization of cervical cancer cells to an ionic DNA-binding cytotoxin by activation of P2Y receptors. FEBS Lett 589:1498–1504CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zheng N, Yin L, Song Z, Ma L, Tang H, Gabrielson NP, Lu H, Cheng J (2014) Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting. Biomaterials 35:1302–1314CrossRefPubMedGoogle Scholar
  16. 16.
    Manthorpe M, Cornefert-Jensen F, Hartikka J, Felgner J, Rundell A, Margalith M, Dwarki V (1993) Gene therapy by intramuscular injection of plasmid DNA: studies on firefly luciferase gene expression in mice. Hum Gene Ther 4:419–431CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemistry and Biomolecular SciencePotsdamUSA

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