Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
Copyright policy )Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer
AbstractTumour 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.
- UCB Pharma (United Kingdom) United Kingdom
- Broad Institute United States
- UCB Pharma (United States) United States
- UCB Pharma (Belgium) Belgium
- University of South Carolina United States
Male, isolation & purification, Neutrophils, Anti-Inflammatory Agents, Tumor Necrosis Factor-alpha (antagonists & inhibitors, Crystallography, X-Ray, Neutrophils (drug effects, immunology, Mice, Receptors, Drug Discovery, Protein Stability (drug effects), Signal Transduction (drug effects, Crystallography, metabolism), Protein Stability, Q, Quaternary (drug effects), Neutrophil Infiltration (drug effects), Recombinant Proteins, Treatment Outcome, Neutrophil Infiltration, therapeutic use), Receptors, Tumor Necrosis Factor, Type I, Screening, Structure-based drug design, Type I (immunology, Public Health Education and Promotion, Signal Transduction, Protein Structure, 570, Science, Recombinant Proteins (isolation & purification, Molecular Dynamics Simulation, Article, Cell Line, Structure-Activity Relationship, Protein Multimerization (drug effects), Animals, Drug discovery and development, Protein Structure, Quaternary, Experimental (drug therapy, Tumor Necrosis Factor-alpha, Arthritis, ultrastructure), immunology), 540, Arthritis, Experimental, X-Ray, Tumour necrosis factor, Protein Multimerization, Tumor Necrosis Factor, metabolism, Anti-Inflammatory Agents (pharmacology
Male, isolation & purification, Neutrophils, Anti-Inflammatory Agents, Tumor Necrosis Factor-alpha (antagonists & inhibitors, Crystallography, X-Ray, Neutrophils (drug effects, immunology, Mice, Receptors, Drug Discovery, Protein Stability (drug effects), Signal Transduction (drug effects, Crystallography, metabolism), Protein Stability, Q, Quaternary (drug effects), Neutrophil Infiltration (drug effects), Recombinant Proteins, Treatment Outcome, Neutrophil Infiltration, therapeutic use), Receptors, Tumor Necrosis Factor, Type I, Screening, Structure-based drug design, Type I (immunology, Public Health Education and Promotion, Signal Transduction, Protein Structure, 570, Science, Recombinant Proteins (isolation & purification, Molecular Dynamics Simulation, Article, Cell Line, Structure-Activity Relationship, Protein Multimerization (drug effects), Animals, Drug discovery and development, Protein Structure, Quaternary, Experimental (drug therapy, Tumor Necrosis Factor-alpha, Arthritis, ultrastructure), immunology), 540, Arthritis, Experimental, X-Ray, Tumour necrosis factor, Protein Multimerization, Tumor Necrosis Factor, metabolism, Anti-Inflammatory Agents (pharmacology
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).92 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!