2. Academic Validation
  3. Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a

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

  • Nat Commun. 2017 Aug 24;8(1):351. doi: 10.1038/s41467-017-00414-w.
Rink-Jan Lohman 1 2 3,  Johan K Hamidon 1 3,  Robert C Reid 1 2 3,  Jessica A Rowley 1 2 3,  Mei-Kwan Yau 1 3,  Maria A Halili 1 3,  Daniel S Nielsen 1 3,  Junxian Lim 1 2 3,  Kai-Chen Wu 1 2 3,  Zhixuan Loh 1 2 3,  Anh Do 1 2 3,  Jacky Y Suen 1 2 3,  Abishek Iyer 4 5 6,  David P Fairlie 7 8 9
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 2 Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 3 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, 4072, Australia.
  • 4 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. a.iyer@imb.uq.edu.au.
  • 5 Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. a.iyer@imb.uq.edu.au.
  • 6 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, 4072, Australia. a.iyer@imb.uq.edu.au.
  • 7 Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia. d.fairlie@imb.uq.edu.au.
  • 8 Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD, 4072, Australia. d.fairlie@imb.uq.edu.au.
  • 9 Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, QLD, 4072, Australia. d.fairlie@imb.uq.edu.au.
PMID: 28839129 DOI: 10.1038/s41467-017-00414-w
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 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.Complement C3a is an important protein in innate and adaptive immunity, but its roles in vivo are unclear. Here the authors develop novel chemical agonists and antagonists for the C3a receptor, and show that they modulate mast cell degranulation and inflammation in a rat paw edema model.

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