Title : Screening of new peptidomimetics based on kinase-inhibitory region of suppressors of cytokine signaling 1 as anti-inflammatory agents
SOCS (Suppressor Of Cytokine Signalling) proteins are negative feedback regulators of the JAK (Janus kinase)/STAT (Signal Transducer And Activator Of Transcription) pathway. Their expression levels are low under physiological conditions, but they are up-regulated in response to cytokine stimulation in many immune and inflammatory processes. Unlike the other SOCS proteins, SOCS1 and SOCS3 show a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Drug discovery processes of compounds based on KIR sequence developed a peptidomimetic called PS5, as lead compound resulting promising in functional in vitro and in inflammatory animal models. On the basis of this lead compound, several peptidomimetics have been designed bearing new structural constraints that were analyzed in both affinities toward JAK2 (through different biochemical assays) and conformational features through Circular Dichroism and NMR spectroscopies. To shed light on the anti-inflammatory actions of PS5, these compounds have been tested in the most abundant cells of blood vessels involved in inflammatory vascular diseases, VSMCs. These experiments revealed the specificity of action of PS5 as mimetic of the entire SOCS1, since it demonstrated able to reduce STAT1 and STAT3 phosphorylation and their nuclear translocation. Among these mimetics, several cyclic analogues of PS5 showed better anti-inflammatory functions suggesting that the presence of a steric hindrance and aromatic group, as naphthyl group, improves proteases’ resistance. Overall data prompted us to generate more constrained peptides with increased rigidity to build up a model of the pharmacophore, also with the help of docking studies, to design suitable modifications to achieve selective inhibition of JAK2’s activity. As preliminary results, new analogues containing different intramolecular cycles have been designed and tested as new and more potent peptidomimetic of KIR-SOCS1.
Presentation Learning Outcome
• The audience will greatly appreciate this simple low-cost strategy for developing lead compounds with high affinities towards targets.
• The audience will be able to understand the benefits in multidisciplinary approaches to the screening of new active molecules.