SMALL MOLECULE INHIBITORS OF CD40-TRAF6 INTERACTIONS
- New selective inhibitors for treatment of chronic inflammatory diseases, such as atherosclerosis, obesity and multiple sclerosis.
- Inhibitors selectively block CD40-TRAF6 interactions
- The selective blockage of the CD40-TRAF6 interactions strongly reduces inflammation, whereas unwanted immune-suppressive side effects are reduced
The co-stimulatory CD40-CD40L dyad is crucial in the development and progression of immune re- sponses and chronic inflammatory diseases, such as atherosclerosis, obesity and multiple sclerosis. However, long-term antibody-mediated inhibition of CD40L or CD40 is not clinically feasible as it re- sults in thromboembolic events and severe immune suppression. More downstream inhibition of the CD40L-CD40 pathway is therefore preferable, especially tumor necrosis factor receptor-associated fac- tors (TRAFs) recruited by CD40.
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Several TRAF knock-out mouse models indicated that CD40-TRAF6 interactions play an essential role in inflammatory diseases. Here a set of inhibitors that selectively block CD40-TRAF6 interactions is presented. The rest of the CD40 cascade is left unaffected preventing unwanted immune-suppressive sideeffects.
The new inhibitors offer promising candidates as therapeutic agents for the treatment of chronic in- flammatory diseases, such as atherosclerosis, obesity and multiple sclerosis. The selective blockage of the CD40-TRAF6 interactions therefore strongly reduces inflammation, whereas unwanted immu- ne-suppressive side effects are limited.