Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

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 thera...

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Veröffentlicht in:	Nature communications Jg. 10; H. 1; S. 5795 - 12
Hauptverfasser:	O’Connell, James, Porter, John, Kroeplien, Boris, Norman, Tim, Rapecki, Stephen, Davis, Rachel, McMillan, David, Arakaki, Tracy, Burgin, Alex, Fox III, David, Ceska, Tom, Lecomte, Fabien, Maloney, Alison, Vugler, Alex, Carrington, Bruce, Cossins, Benjamin P, Bourne, Tim, Lawson, Alastair
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 19.12.2019 Nature Publishing Group Nature Portfolio
Schlagworte:	631/154/309/2144 631/154/309/2420 631/154/309/507 Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Arthritis Arthritis, Experimental - drug therapy Arthritis, Experimental - immunology Asymmetry Autoimmune diseases Cell Line Crohn's disease Crystallography, X-Ray Cytokines Drug development Drug Discovery Drugs Humanities and Social Sciences Male Mice Molecular Dynamics Simulation multidisciplinary Neutrophil Infiltration - drug effects Neutrophils - drug effects Neutrophils - immunology Protein interaction Protein Multimerization - drug effects Protein Stability - drug effects Protein Structure, Quaternary - drug effects Proteins Receptors, Tumor Necrosis Factor, Type I - immunology Receptors, Tumor Necrosis Factor, Type I - metabolism Recombinant Proteins - isolation & purification Recombinant Proteins - metabolism Recombinant Proteins - ultrastructure Rheumatoid arthritis Science Science (multidisciplinary) Signal Transduction - drug effects Signal Transduction - immunology Signaling Structure-Activity Relationship Treatment Outcome Trimers Tumor necrosis factor Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - immunology Tumor Necrosis Factor-alpha - isolation & purification Tumor Necrosis Factor-alpha - metabolism Tumor Necrosis Factor-alpha - ultrastructure Tumor necrosis factor-TNF Tumors
ISSN:	2041-1723, 2041-1723
Online-Zugang:	Volltext
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Zusammenfassung:	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. While biologics have been successfully applied in TNF antagonist treatments, there are no clinically approved small molecules that target TNF. Here, the authors discover potent small molecule inhibitors of TNF, elucidate their molecular mechanism, and demonstrate TNF inhibition in vitro and in vivo.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-13616-1