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ph‐Triggered Transport of Molecules into Cells by Transmembrane Helix Insertion
Author(s) -
Engelman Donald M.,
Andreev Oleg,
Reshetnyak Yana K.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a457-b
Subject(s) - cytoplasm , chemistry , biophysics , peptide , transmembrane protein , cell membrane , cancer cell , cell , membrane , transmembrane domain , actin , microbiology and biotechnology , biochemistry , biology , cancer , receptor , genetics
We have developed a peptide that enables injection of molecules into a target cell at acidic pH, but not at normal, physiological pH. The process is driven by a previously discovered water‐soluble peptide that inserts itself into the plasma membrane and forms a transbilayer helix at pH < 7.0 1 , and we have conducted a number of biophysical measurements that show it can insert as a monomer with its C‐terminus in the cytoplasm. A therapeutic or imaging agent bound to the C‐ terminus via a disulfide link can be delivered to the cytoplasm of a target cell, where the reducing environment cleaves the disulfide. We show the injection of fluorescent dyes into cancer cells at pH 5.5–6.5, whereas only traces of dye are observed on the outer side of the membrane at pH 7.4. Likewise, the cell‐impermeable toxin phalloidin is translocated and released, inducing stabilization of the actin cytoskeleton and inhibition of cell contractility. The peptide might be used to deliver drugs or imaging agents to cells in the acidic environment that is created in many diseased tissues, for example in cancer, atherosclerosis, inflammation, heart infarction or stroke. This work was supported by grants from the NIH (GM22778 and GM070895) and the NSF (MCB9406983) to D.M.E.