Rational Control of Protein-Protein Interactions with Protein-ATRP-Generated Protease-Sensitive Polymer Cages
Kaupbayeva B. Murata H. Rule G.S. Matyjaszewski K. Russell A.J.
12 September 2022American Chemical Society
Biomacromolecules
2022#23Issue 93831 - 3846 pp.
Protease-protease interactions lie at the heart of the biological cascades that provide rapid molecular responses to living systems. Blood clotting cascades, apoptosis signaling networks, bacterial infection, and virus trafficking have all evolved to be activated and sustained by protease-protease interactions. Biomimetic strategies designed to target drugs to specific locations have generated proprotein drugs that can be activated by proteolytic cleavage to release native protein. We have previously demonstrated that the modification of enzymes with a custom-designed comb-shaped polymer nanoarmor can shield the enzyme surface and eliminate almost all protein-protein interactions. We now describe the synthesis and characterization of protease-sensitive comb-shaped nanoarmor cages using poly(ethylene glycol) methacrylate macromonomers where the PEG tines of the comb are connected to the backbone of the growing polymer chain by peptide linkers. Protease-induced cleavage of the tines of the comb releases a polymer-modified protein that can once again participate in protein-protein interactions. Atom transfer radical polymerization (ATRP) was used to copolymerize the macromonomer and carboxybetaine methacrylate from initiator-labeled chymotrypsin and trypsin enzymes, yielding proprotease conjugates that retained activity toward small peptide substrates but prevented activity against proteins. Native proteases triggered the release of the PEG side chains from the polymer backbone within 20 min, thereby increasing the activity of the conjugate toward larger protein substrates by 100%. Biomimetic cascade initiation of nanoarmored protease-sensitive protein-polymer conjugates may open the door to a new class of responsive targeted therapies.
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Department of Biological Sciences, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, 15213, PA, United States
Center for Polymer-Based Protein Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, 15213, PA, United States
National Laboratory Astana, Nazarbayev University, Nur-Sultan City, 010000, Kazakhstan
Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, 15213, PA, United States
Department of Chemical Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, 15213, PA, United States
Amgen, 1 Amgen Center Drive, Thousand Oaks, 91320, CA, United States
Department of Biological Sciences
Center for Polymer-Based Protein Engineering
National Laboratory Astana
Department of Chemistry
Department of Chemical Engineering
Amgen
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