Spontaneous membrane-translocating peptides by orthogonal high-throughput screening

Jessica R. Marks, Jesse Placone, Kalina Hristova, William C. Wimley

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


Combinatorial peptide chemistry and orthogonal high-throughput screening were used to select peptides that spontaneously translocate across synthetic lipid bilayer membranes without permeabilization. A conserved sequence motif was identified that contains several cationic residues in conserved positions in an otherwise hydrophobic sequence. This 9-residue motif rapidly translocates across synthetic multibilayer vesicles and into cells while carrying a large polar dye as a "cargo" moiety. The extraordinary ability of this family of peptides to spontaneously translocate across bilayers without an energy source of any kind is distinctly different from the behavior of the well-known, highly cationic cell-penetrating peptides, such as the HIV tat peptide, which do not translocate across synthetic bilayers, and enter cells mostly by active endocytosis. Peptides that translocate spontaneously across membranes have the potential to transform the field of drug design by enabling the delivery of otherwise membrane-impermeant polar drugs into cells and tissues. Here we describe the chemical tools needed to rapidly identify spontaneous membrane translocating peptides.

Original languageEnglish (US)
Pages (from-to)8995-9004
Number of pages10
JournalJournal of the American Chemical Society
Issue number23
StatePublished - Jun 15 2011

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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