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Receptor–Ligand Kinetics Influence the Mechanism of Action of Covalently Linked TLR Ligands

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    Receptor–Ligand Kinetics Influence the Mechanism of Action of Covalently Linked TLR Ligands
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    • Flora W. Kimani
      Flora W. Kimani
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
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    • Jainu Ajit
      Jainu Ajit
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
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    • Alexander Galluppi
      Alexander Galluppi
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
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    • Saikat Manna
      Saikat Manna
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
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      Orcidhttp://orcid.org/0000-0002-0809-5695
    • William J. Howitz
      William J. Howitz
      Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025, United States
      More by William J. Howitz
      Orcidhttp://orcid.org/0000-0001-6323-7126
    • Sophia Tang
      Sophia Tang
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
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    • Aaron P. Esser-Kahn*
      Aaron P. Esser-Kahn
      Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United States
      *E-mail: [email protected]
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      Orcidhttp://orcid.org/0000-0003-1273-0951
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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2021, 16, 2, 380–388
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    https://doi.org/10.1021/acschembio.0c00924
    Published February 1, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    We report a mechanistic study comparing the immune activation of conjugated Toll-like receptor (TLR) agonists and their unlinked mixtures. Herein, we synthesized a set of six linked dual agonists with different ligands, molecular structures, receptor locations, and biophysical characteristics. With these dimers, we ran a series of in vitro cell-based assays, comparing initial and overall NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation, cytokine expression profiles, as well as time-resolved TNF-α (Tumor Necrosis Factor alpha) expression. We show that initial activation kinetics, ligand specificity, and the dose of the agonist influence the activity of these linked TLR systems. These results can help improve vaccine design by showing how linked TLR agonists can improve their potency with the appropriate selection of key criteria.

    Copyright © 2021 American Chemical Society

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.0c00924.

    • Synthesis of conjugated agonists and heterodimers, characterization, and additional cell assay data (PDF)

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    This article is cited by 5 publications.

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    ACS Chemical Biology

    Cite this: ACS Chem. Biol. 2021, 16, 2, 380–388
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acschembio.0c00924
    Published February 1, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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