Reactive Self-Assembly of Polymers and Proteins to Reversibly Silence a Killer Protein

Biomacromolecules
Judy VenturaS Thayumanavan

Abstract

Conjugation of biologically active proteins to polymeric materials is of great interest in the treatment of cancer and other diseases of protein deficiency. The conjugation of such biomacromolecules is challenging both due to their hydrophilicity and propensity to denature under non-native conditions. We describe a novel reactive self-assembly approach to "wrap" a protein with polymers, simultaneously protecting its delicate folded state and silencing its enzymatic activity. This approach has been demonstrated using caspase-3, an apoptosis-inducing protein, as the first case study. The protein-polymer conjugation is designed to be reversed under the native conditions for caspase-3, that is, the reducing environment found in the cytosol. The current strategy allowed release and recovery of up to 86% of caspase activity and nanogel-caspase-3 conjugates induced 70-80% apoptotic cell death shortly thereafter. This approach is widely generalizable and should be applicable to the intracellular delivery of a wide range of therapeutic proteins for treatment of complex and genetic diseases.

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Citations

Apr 14, 2017·Journal of the American Chemical Society·Kingshuk DuttaS Thayumanavan
May 8, 2020·Small·Nan ZhangYanli Zhao
Mar 25, 2017·Nanomedicine·Moumita RayVincent M Rotello
Nov 10, 2020·Protein Science : a Publication of the Protein Society·Francesca AnsonJeanne A Hardy
Feb 17, 2021·Biomacromolecules·Francesca AnsonS Thayumanavan
Jan 1, 2020·Israel Journal of Chemistry·Ziwen Jiang, S Thayumanavan
Aug 10, 2017·Biomacromolecules·Ulyana ShimanovichTuomas P J Knowles
Oct 21, 2017·Molecular Pharmaceutics·Kishore RaghupathiS Thayumanavan
Nov 17, 2017·Biomacromolecules·Celia C HomyakS Thayumanavan
Jul 2, 2021·Advanced Materials·Meng LiPeng Huang
Jul 21, 2017·Biochemistry·Kevin B DagbayJeanne A Hardy

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