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Title: Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation

Abstract

Peptides synthesized in the likeness of their native interaction domain(s) are natural choices to target protein protein interactions (PPIs) due to their fidelity of orthostatic contact points between binding partners. Despite therapeutic promise, intracellular delivery of biofunctional peptides at concentrations necessary for efficacy remains a formidable challenge. Peptide amphiphiles (PAs) provide a facile method of intracellular delivery and stabilization of bioactive peptides. PAs consisting of biofunctional peptide headgroups linked to hydrophobic alkyl lipid-like tails prevent peptide hydrolysis and proteolysis in circulation, and PA monomers are internalized via endocytosis. However, endocytotic sequestration and steric hindrance from the lipid tail are two major mechanisms that limit PA efficacy to target intracellular PPIs. To address these problems, we have constructed a PA platform consisting of cathepsin-B cleavable PAs in which a selective p53-based inhibitory peptide is cleaved from its lipid tail within endosomes, allowing for intracellular peptide accumulation and extracellular recycling of the lipid moiety. We monitor for cleavage and follow individual PA components in real time using a resonance energy transfer (FRET)-based tracking system. Using this platform, components in real time using a Forster we provide a better understanding and quantification of cellular internalization, trafficking, and endosomal cleavage of PAs and ofmore » the ultimate fates of each component.« less

Authors:
 [1];  [1];  [2];  [3];  [3];  [4]; ORCiD logo [5]
  1. Institute for Molecular Engineering, University of Chicago, Eckardt Research Center, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, 900 East 57th Street, KCBD 5122, Chicago, Illinois 60637, United States
  2. Institute for Molecular Engineering, University of Chicago, Eckardt Research Center, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States; Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, 900 East 57th Street, KCBD 5122, Chicago, Illinois 60637, United States; Medical Scientist Training Program, University of Chicago, 924 East 57th Street, Suite 104, Chicago, Illinois 60637, United States
  3. Institute for Molecular Engineering, University of Chicago, Eckardt Research Center, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States
  4. Institute for Molecular Engineering, University of Chicago, Eckardt Research Center, 5640 South Ellis Avenue, Chicago, Illinois 60637, United States; Institute for Molecular Engineering, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60639, United States
  5. Department of Pediatrics, Section of Hematology/Oncology, University of Chicago, 900 East 57th Street, KCBD 5122, Chicago, Illinois 60637, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science - Office of Basic Energy Sciences - Materials Sciences and Engineering Division
OSTI Identifier:
1421656
DOE Contract Number:
AC02-06CH11357
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioconjugate Chemistry; Journal Volume: 28; Journal Issue: 9
Country of Publication:
United States
Language:
English

Citation Formats

Acar, Handan, Samaeekia, Ravand, Schnorenberg, Mathew R., Sasmal, Dibyendu K., Huang, Jun, Tirrell, Matthew V., and LaBelle, James L. Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation. United States: N. p., 2017. Web. doi:10.1021/acs.bioconjchem.7b00364.
Acar, Handan, Samaeekia, Ravand, Schnorenberg, Mathew R., Sasmal, Dibyendu K., Huang, Jun, Tirrell, Matthew V., & LaBelle, James L. Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation. United States. doi:10.1021/acs.bioconjchem.7b00364.
Acar, Handan, Samaeekia, Ravand, Schnorenberg, Mathew R., Sasmal, Dibyendu K., Huang, Jun, Tirrell, Matthew V., and LaBelle, James L. Thu . "Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation". United States. doi:10.1021/acs.bioconjchem.7b00364.
@article{osti_1421656,
title = {Cathepsin-Mediated Cleavage of Peptides from Peptide Amphiphiles Leads to Enhanced Intracellular Peptide Accumulation},
author = {Acar, Handan and Samaeekia, Ravand and Schnorenberg, Mathew R. and Sasmal, Dibyendu K. and Huang, Jun and Tirrell, Matthew V. and LaBelle, James L.},
abstractNote = {Peptides synthesized in the likeness of their native interaction domain(s) are natural choices to target protein protein interactions (PPIs) due to their fidelity of orthostatic contact points between binding partners. Despite therapeutic promise, intracellular delivery of biofunctional peptides at concentrations necessary for efficacy remains a formidable challenge. Peptide amphiphiles (PAs) provide a facile method of intracellular delivery and stabilization of bioactive peptides. PAs consisting of biofunctional peptide headgroups linked to hydrophobic alkyl lipid-like tails prevent peptide hydrolysis and proteolysis in circulation, and PA monomers are internalized via endocytosis. However, endocytotic sequestration and steric hindrance from the lipid tail are two major mechanisms that limit PA efficacy to target intracellular PPIs. To address these problems, we have constructed a PA platform consisting of cathepsin-B cleavable PAs in which a selective p53-based inhibitory peptide is cleaved from its lipid tail within endosomes, allowing for intracellular peptide accumulation and extracellular recycling of the lipid moiety. We monitor for cleavage and follow individual PA components in real time using a resonance energy transfer (FRET)-based tracking system. Using this platform, components in real time using a Forster we provide a better understanding and quantification of cellular internalization, trafficking, and endosomal cleavage of PAs and of the ultimate fates of each component.},
doi = {10.1021/acs.bioconjchem.7b00364},
journal = {Bioconjugate Chemistry},
number = 9,
volume = 28,
place = {United States},
year = {Thu Aug 24 00:00:00 EDT 2017},
month = {Thu Aug 24 00:00:00 EDT 2017}
}