TY - JOUR
T1 - pH-triggered, macromolecule-sized poration of lipid bilayers by synthetically evolved peptides
AU - Wiedman, Gregory
AU - Kim, Sarah Y.
AU - Zapata-Mercado, Elmer
AU - Wimley, William C.
AU - Hristova, Kalina
N1 - Funding Information:
This work was supported by NIH grants GM068619 (K.H.) and GM111824 (W.C.W.). We thank Jing He, Taylor Fuselier, W. Berkeley Kauffman, Charles G. Starr, and Hussain Badani for early brainstorming on the library design.
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2017/1/18
Y1 - 2017/1/18
N2 - PH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration. The peptides we selected are remarkably potent macromolecular sized pore-formers at pH 5, while having little or no activity at pH 7, as intended. The action of these peptides likely relies on tight coupling between membrane partitioning, α-helix formation, and electrostatic repulsions between acidic side chains, which collectively drive a sharp pH-triggered transition between inactive and active configurations with apparent pKa values of 5.5-5.8. This work opens new doors to developing applications that utilize peptides with membrane-permeabilizing activities that are triggered by physiologically relevant decreases in pH.
AB - PH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration. The peptides we selected are remarkably potent macromolecular sized pore-formers at pH 5, while having little or no activity at pH 7, as intended. The action of these peptides likely relies on tight coupling between membrane partitioning, α-helix formation, and electrostatic repulsions between acidic side chains, which collectively drive a sharp pH-triggered transition between inactive and active configurations with apparent pKa values of 5.5-5.8. This work opens new doors to developing applications that utilize peptides with membrane-permeabilizing activities that are triggered by physiologically relevant decreases in pH.
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U2 - 10.1021/jacs.6b11447
DO - 10.1021/jacs.6b11447
M3 - Article
C2 - 28001058
AN - SCOPUS:85019161180
SN - 0002-7863
VL - 139
SP - 937
EP - 945
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 2
ER -