title: Peptides displayed as high density brush polymers resist proteolysis and retain bioactivity.
abstract: We describe a strategy for rendering peptides resistant to proteolysis by formulating them as high-density brush polymers. The utility of this approach is demonstrated by polymerizing well-established cell-penetrating peptides (CPPs) and showing that the resulting polymers are not only resistant to proteolysis but also maintain their ability to enter cells. The scope of this design concept is explored by studying the proteolytic resistance of brush polymers composed of peptides that are substrates for either thrombin or a metalloprotease. Finally, we demonstrate that the proteolytic susceptibility of peptide brush polymers can be tuned by adjusting the density of the polymer brush and offer in silico models to rationalize this finding. We contend that this strategy offers a plausible method of preparing peptides for in vivo use, where rapid digestion by proteases has traditionally restricted their utility.
authors.affiliation: Department of Chemistry & Biochemistry, ‡Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego , La Jolla, California 92093, United States.
authors.forename: Angela P
authors.initials: AP
authors.lastname: Blum
authors.forename: Jacquelin K
authors.initials: JK
authors.lastname: Kammeyer
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
authors.forename: Dustin T
authors.initials: DT
authors.lastname: Crystal
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Gianneschi
mesh_terms: D000595:Amino Acid Sequence; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles / Q000737:chemistry; D010447:Peptide Hydrolases / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D011487:Protein Conformation; D021381:Protein Transport; D059748:Proteolysis
chemical_list: D057846:Cell-Penetrating Peptides; D011108:Polymers; D010447:Peptide Hydrolases