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Stapled β-Hairpins Featuring 4-Mercaptoproline
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    Stapled β-Hairpins Featuring 4-Mercaptoproline
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    • Jennifer R. Pace
      Jennifer R. Pace
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    • Bryan J. Lampkin
      Bryan J. Lampkin
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    • Charles Abakah
      Charles Abakah
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    • Adam Moyer
      Adam Moyer
      Molecular Engineering and Sciences Institute, University of Washington, Seattle Washington 98195, United States
      More by Adam Moyer
    • Jiayuan Miao
      Jiayuan Miao
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
      More by Jiayuan Miao
    • Kirsten Deprey
      Kirsten Deprey
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    • Robert A. Cerulli
      Robert A. Cerulli
      Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United States
    • Yu-Shan Lin
      Yu-Shan Lin
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
      More by Yu-Shan Lin
    • James D. Baleja
      James D. Baleja
      Graduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United States
    • David Baker
      David Baker
      Molecular Engineering and Sciences Institute, University of Washington, Seattle Washington 98195, United States
      Department of Biochemistry, Institute for Protein Design, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, United States
      More by David Baker
    • Joshua A. Kritzer*
      Joshua A. Kritzer
      Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
      *[email protected]
    Other Access OptionsSupporting Information (4)

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2021, 143, 37, 15039–15044
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    https://doi.org/10.1021/jacs.1c04378
    Published September 13, 2021
    Copyright © 2021 American Chemical Society

    Abstract

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    Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel β-strands, and then we incorporated that staple within a β-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein–protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein–protein interactions.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.1c04378.

    • Results from simulations informed by NMR data (ZIP)

    • Designed structure (PDB)

    • Original code (ZIP)

    • Experimental and computational methods, information on peptide synthesis and characterization, additional CD data and thermal melts, and NMR data sets including variable temperature experiments, simulated annealing methodology, and results (PDF)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

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    This article is cited by 14 publications.

    1. Colin S. Swenson, Gunasheil Mandava, Deborah M. Thomas, Raymond E. Moellering. Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics. Chemical Reviews 2024, 124 (22) , 13020-13093. https://doi.org/10.1021/acs.chemrev.4c00423
    2. Bohan Ma, Donghua Liu, Mengjun Zheng, Zhe Wang, Dize Zhang, Yanlin Jian, Jian Ma, Yizeng Fan, Yule Chen, Yang Gao, Jing Liu, Xiang Li, Lei Li. Development of a Double-Stapled Peptide Stabilizing Both α-Helix and β-Sheet Structures for Degrading Transcription Factor AR-V7. JACS Au 2024, 4 (2) , 816-827. https://doi.org/10.1021/jacsau.3c00795
    3. Brice A. Ludwig, Christina R. Forbes, Neal J. Zondlo. N-Terminal Proline Editing for the Synthesis of Peptides with Mercaptoproline and Selenoproline: Mechanistic Insights Lead to Greater Efficiency in Proline Native Chemical Ligation. ACS Chemical Biology 2024, 19 (2) , 536-550. https://doi.org/10.1021/acschembio.3c00705
    4. Hawley Brown, Mia Chung, Alina Üffing, Nefeli Batistatou, Tiffany Tsang, Samantha Doskocil, Weiqun Mao, Dieter Willbold, Robert C. Bast, Jr., Zhen Lu, Oliver H. Weiergräber, Joshua A. Kritzer. Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy. Journal of the American Chemical Society 2022, 144 (32) , 14687-14697. https://doi.org/10.1021/jacs.2c04699
    5. John D. M. Nguyen, Gabriel C. A. da Hora, Marcus C. Mifflin, Andrew G. Roberts, Jessica M. J. Swanson. Tying the Knot: In Silico Design of Foldable Lasso Peptides. 2025https://doi.org/10.1101/2025.01.17.633674
    6. Dominika Nielipińska, Dominika Rubiak, Agnieszka J. Pietrzyk-Brzezińska, Joanna Małolepsza, Katarzyna M. Błażewska, Edyta Gendaszewska-Darmach. Stapled peptides as potential therapeutics for diabetes and other metabolic diseases. Biomedicine & Pharmacotherapy 2024, 180 , 117496. https://doi.org/10.1016/j.biopha.2024.117496
    7. Vardhan Satalkar, Gemechis D. Degaga, Wei Li, Yui Tik Pang, Andrew C. McShan, James C. Gumbart, Julie C. Mitchell, Matthew P. Torres. Generative β-hairpin design using a residue-based physicochemical property landscape. Biophysical Journal 2024, 123 (17) , 2790-2806. https://doi.org/10.1016/j.bpj.2024.01.029
    8. Frances R. Smith, Declan Meehan, Rhys C. Griffiths, Harriet J. Knowles, Peiyu Zhang, Huw E. L. Williams, Andrew J. Wilson, Nicholas J. Mitchell. Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation. Chemical Science 2024, 15 (25) , 9612-9619. https://doi.org/10.1039/D3SC05865D
    9. Qian Zhang, Ziyang Wang, Xiaohan Mei, Quan Chen, Chunqiu Zhang. Stapled peptides: targeting protein-protein interactions in drug development. Exploration of Drug Science 2024, , 154-189. https://doi.org/10.37349/eds.2024.00041
    10. Chao Zhang, Fenfen Liu, Youming Zhang, Chun Song. Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle. European Journal of Medicinal Chemistry 2024, 268 , 116234. https://doi.org/10.1016/j.ejmech.2024.116234
    11. Jiongjia Cheng, Junlong Zhou, Lingyan Kong, Haiying Wang, Yuchi Zhang, Xiaofeng Wang, Guangxiang Liu, Qian Chu. Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation. RSC Medicinal Chemistry 2023, 14 (12) , 2496-2508. https://doi.org/10.1039/D3MD00487B
    12. Teodors Pantelejevs, Pedro Zuazua-Villar, Oliwia Koczy, Andrew J. Counsell, Stephen J. Walsh, Naomi S. Robertson, David R. Spring, Jessica A. Downs, Marko Hyvönen. A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase. Chemical Science 2023, 14 (47) , 13915-13923. https://doi.org/10.1039/D3SC03331G
    13. Nefeli Batistatou, Joshua A. Kritzer. Investigation of Sequence‐Penetration Relationships of Antisense Oligonucleotides. ChemBioChem 2023, 24 (9) https://doi.org/10.1002/cbic.202300009
    14. Teodors Pantelejevs, Pedro Zuazua-Villar, Oliwia Koczy, Andrew Counsell, Stephen J. Walsh, Naomi S. Robertson, David R. Spring, Jessica Downs, Marko Hyvönen. A Recombinant Approach For Stapled Peptide Discovery Yields Inhibitors of the RAD51 Recombinase. 2023https://doi.org/10.1101/2023.02.24.529929
    15. Eric Valeur. New Therapeutic Chemical Modalities: Compositions, Modes-of-action, and Drug Discovery. 2023, 911-961. https://doi.org/10.1039/9781788018982-00911
    16. JOE R. CANNON, PRAKASH VACHASPATI, YANG YUAN. A Comprehensive Picture of Biotransformation in Drug Discovery. 2022, 41-101. https://doi.org/10.1002/9781119851042.ch4

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2021, 143, 37, 15039–15044
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.1c04378
    Published September 13, 2021
    Copyright © 2021 American Chemical Society

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