| Autor: |
David A. Fox, Bruce Carrington, Rachel Davis, Alex Vugler, John Robert Porter, Timothy John Norman, Benjamin P. Cossins, Boris Kroeplien, Fabien Claude Lecomte, David McMillan, Alastair D. G. Lawson, Alex B. Burgin, Tim Bourne, Stephen Edward Rapecki, Tom Ceska, O'connell James Philip, Alison Maloney, Tracy Arakaki |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 10, Iss 1, Pp 1-12 (2019) |
| ISSN: |
2041-1723 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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