Animals; Anti-Inflammatory Agents (pharmacology, therapeutic use); Arthritis, Experimental (drug therapy, immunology); Cell Line; Crystallography, X-Ray; Drug Discovery; Male; Mice; Molecular Dynamics Simulation; Neutrophil Infiltration (drug effects); Neutrophils (drug effects, immunology); Protein Multimerization (drug effects); Protein Stability (drug effects); Protein Structure, Quaternary (drug effects); Receptors, Tumor Necrosis Factor, Type I (immunology, metabolism); Recombinant Proteins (isolation & purification, metabolism, ultrastructure); Signal Transduction (drug effects, immunology); Structure-Activity Relationship; Treatment Outcome; Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology, isolation & purification, metabolism, ultrastructure)
Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein-protein interactions.
Digital Object Identifier (DOI)
Nature Communications, Volume 10, Issue 5795, 2019.
© The Author(s) 2019 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
O’Connell, J., Porter, J., Kroeplien, B., Norman, T., Rapecki, S., Davis, R., McMillan, D., Arakaki, T., Burgin, A., Fox III, D., Ceska, T., Lecomte, F., Maloney, A., Vugler, A., Carrington, B., Cossins, B. P., Bourne, T., & Lawson, A. (2019). Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the Trimer. Nature Communications, 10(5795). https://doi.org/10.1038/s41467-019-13616-1