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

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, Do, Anh, Suen, Jacky Y., Iyer, Abishek and Fairlie, David P. (2017) Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a. Nature Communications, 8 1: 351. doi:10.1038/s41467-017-00414-w


Author 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
Do, Anh
Suen, Jacky Y.
Iyer, Abishek
Fairlie, David P.
Title Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2017-12-01
Year available 2017
Sub-type Article (original research)
DOI 10.1038/s41467-017-00414-w
Open Access Status DOI
Volume 8
Issue 1
Start page 351
Total pages 15
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Multidisciplinary sciences
Science & technology - other topics
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1028423
1084018
DP130100629
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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