A Novel Soluble Peptide with pH-Responsive Membrane Insertion.
Several diseases, such as cancer, are characterized by acidification of the extracellular environment. Acidosis can be employed as a target to specifically direct therapies to the diseased tissue. We have used first principles to design an acidity-triggered rational membrane (ATRAM) peptide with high solubility in solution that is able to interact with lipid membranes in a pH-dependent fashion. Biophysical studies show that the ATRAM peptide binds to the surface of lipid membranes at pH 8.0. However, acidification leads to the peptide inserting into the lipid bilayer as a transmembrane α-helix. The insertion of ATRAM into membranes occurs at a moderately acidic pH (with a pK of 6.5), similar to the extracellular pH found in solid tumors. Studies with human cell lines showed a highly efficient pH-dependent membrane targeting, without causing toxicity. Here we show that it is possible to rationally design a soluble peptide that selectively targets cell membranes in acidic environments.
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
Vanessa P
VP
Nguyen
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
Daiane S
DS
Alves
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
Haden L
HL
Scott
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
Forrest L
FL
Davis
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee , Knoxville, Tennessee 37996, United States.
Francisco N
FN
Barrera
D000595:Amino Acid Sequence; D055592:Biophysical Phenomena; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008563:Membrane Lipids / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D011487:Protein Conformation; D012995:Solubility
D004337:Drug Carriers; D008563:Membrane Lipids; D010455:Peptides