Context

Signal transduction by the Toll-like receptors (TLRs) is central to host defense against many pathogenic microorganisms and also underlies a large burden of human diseases, including chronic inflammatory disorders. TLRs activation induces a cascade of downstream signal transducer interactions that promote the assembly of a multiproteic complex, namely the 'Myddosome' complex, activate the nuclear factorκB (NF-κB), and lead to the production of pro-inflammatory cytokines (TNFα, IL-1β, IL-6…).

Benefits

Using rational design, the team has synthesized different stapled peptides inhibitors of Myddosome assembly. Stapled peptides present the advantage not only to be more soluble and stable than linear peptides but also to be able to be cell permeable. The stapled peptides were evaluated in different cell models and have shown their ability to inhibit IL1-b secretion in PMA-stimulated monocytes without blocking differentiation, inhibit IL1-b, TNFa & IL-6 secretion after activation of monocytes by LPS and dose-dependently inhibit ER stress. In vivo studies have also showed the potency of these peptides in different mouse modeles (sepsis, oncology, rhumatoid arthritis).

Applications

These peptides should be highly efficient immunomodulators in inflammatory disorders, auto-immune diseases and oncology.