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Supramolecular Protein Stabilization with Zwitterionic Polypeptide–Cucurbit[7]uril Conjugates

  • Zachary S. Clauss
    Zachary S. Clauss
    Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States
  • Rolande Meudom
    Rolande Meudom
    Department of Pediatrics, Division of Diabetes and Endocrinology, Stanford University, Palo Alto, California 94304, United States
  • Bo Su
    Bo Su
    Department of Chemical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
    More by Bo Su
  • Michael A. VandenBerg
    Michael A. VandenBerg
    Department of Chemical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
  • Simranpreet S. Saini
    Simranpreet S. Saini
    Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States
  • Matthew J. Webber
    Matthew J. Webber
    Department of Chemical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, United States
  • Danny Hung-Chieh Chou
    Danny Hung-Chieh Chou
    Department of Pediatrics, Division of Diabetes and Endocrinology, Stanford University, Palo Alto, California 94304, United States
  • , and 
  • Jessica R. Kramer*
    Jessica R. Kramer
    Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112, United States
    *Email: [email protected]
Cite this: Biomacromolecules 2023, 24, 1, 481–488
Publication Date (Web):December 13, 2022
https://doi.org/10.1021/acs.biomac.2c01319
Copyright © 2022 American Chemical Society

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    Abstract

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    Protein aggregation is an obstacle for the development of new biopharmaceuticals, presenting challenges in shipping and storage of vital therapies. Though a variety of materials and methods have been explored, the need remains for a simple material that is biodegradable, nontoxic, and highly efficient at stabilizing protein therapeutics. In this work, we investigated zwitterionic polypeptides prepared using a rapid and scalable polymerization technique and conjugated to a supramolecular macrocycle host, cucurbit[7]uril, for the ability to inhibit aggregation of model protein therapeutics insulin and calcitonin. The polypeptides are based on the natural amino acid methionine, and zwitterion sulfonium modifications were compared to analogous cationic and neutral structures. Each polymer was end-modified with a single cucurbit[7]uril macrocycle to afford supramolecular recognition and binding to terminal aromatic amino acids on proteins. Only conjugates prepared from zwitterionic structures of sufficient chain lengths were efficient inhibitors of insulin aggregation and could also inhibit aggregation of calcitonin. This polypeptide exhibited no cytotoxicity in human cells even at concentrations that were five-fold of the intended therapeutic regime. We explored treatment of the zwitterionic polypeptides with a panel of natural proteases and found steady biodegradation as expected, supporting eventual clearance when used as a protein formulation additive.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biomac.2c01319.

    • Detailed experimental procedures, spectral data, protease degradation, and related data (PDF)

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    Cited By

    This article is cited by 3 publications.

    1. Ye-Cheng Wang, Si-Cong Bai, Wei-Lin Ye, Jing Jiang, Gao Li. Recent Progress in Site-Selective Modification of Peptides and Proteins Using Macrocycles. Bioconjugate Chemistry 2024, 35 (3) , 277-285. https://doi.org/10.1021/acs.bioconjchem.3c00534
    2. Liufen Kong, Mei Gao, Jiangyan Shi, Chuanzhuang Zhao, Chongyi Chen. Synthetic Polypeptide Bioadhesive Based on Cation−π Interaction and Secondary Structure. ACS Macro Letters 2024, 13 (3) , 361-367. https://doi.org/10.1021/acsmacrolett.4c00075
    3. Yueqi Deng, Binlin Chen, Kongying Zhu, Lixia Ren, Xiaoyan Yuan. Activation of Upper Critical Solution Temperature Behaviors of Zwitterionic Poly(l-methionine-g-poly(sulfobetaine methacrylate)m) with a Bottlebrush Structure. Macromolecules 2024, 57 (1) , 191-200. https://doi.org/10.1021/acs.macromol.3c01920

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