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  • Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a

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    Author(s)
    Lohman, Rink-Jan
    Hamidon, Johan K
    Reid, Robert C
    Rowley, Jessica A
    Yau, Mei-Kwan
    Halili, Maria A
    Nielsen, Daniel S
    Lim, Junxian
    Wu, Kai-Chen
    Loh, Zhixuan
    Anh, Do
    Suen, Jacky Y
    Iyer, Abishek
    Fairlie, David P
    Griffith University Author(s)
    Halili, Maria A.
    Year published
    2017
    Metadata
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    Abstract
    Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti-inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective ...
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    Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti-inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective agonist induces acute rat paw inflammation by first degranulating mast cells before activating macrophages and neutrophils. An orally administered C3a receptor-selective antagonist inhibits mast cell degranulation, thereby blocking recruitment and activation of macrophages and neutrophils, expression of inflammatory mediators and inflammation in a rat paw edema model. These novel tools reveal the mechanism of C3a-induced inflammation and provide new insights to complement-based medicines.
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    Journal Title
    Nature Communications
    Volume
    8
    Issue
    1
    DOI
    https://doi.org/10.1038/s41467-017-00414-w
    Copyright Statement
    © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
    Subject
    Cellular immunology
    Science & Technology
    Multidisciplinary Sciences
    Science & Technology - Other Topics
    DIET-INDUCED OBESITY
    MAST-CELLS
    Publication URI
    http://hdl.handle.net/10072/391504
    Collection
    • Journal articles

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