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Chimeric Peptidomimetics of SOCS 3 Able to Interact with JAK2 as Anti-inflammatory Compounds
journal contribution
posted on 2020-03-27, 21:29 authored by Sara La Manna, Laura Lopez-Sanz, Flavia Anna Mercurio, Sara Fortuna, Marilisa Leone, Carmen Gomez-Guerrero, Daniela MarascoThe immunomodulatory
effects of Suppressor of Cytokine Signaling
(SOCS) proteins, that control the JAK/STAT pathway, indicate them
as attractive candidates for immunotherapies. Recombinant SOCS3 protein
suppresses the effects of inflammation, and its deletion in neurons
or in immune cells increases pathological blood vessels growth. Recently,
on the basis of the structure of the ternary complex among SOCS3,
JAK2, and gp130, we focused on SOCS3 interfacing regions and designed
several interfering peptides (IPs) that were able to mimic SOCS3 biological
role in triple negative breast cancer (TNBC) models. Herein, to explore
other protein regions involved in JAK2 recognition, several new chimeric
peptides connecting noncontiguous SOCS3 regions and including a strongly
aromatic fragment were investigated. Their ability to recognize the
catalytic domain of JAK2 was evaluated through MST (microscale thermophoresis),
and the most promising compound, named KIRCONG chim, exhibited a low
micromolar value for dissociation constant. The conformational features
of chimeric peptides were analyzed through circular dichroism and
NMR spectroscopies, and their anti-inflammatory effects were assessed
in cell cultures. Overall data suggest the importance of aromatic
contribution in the recognition of JAK2 and that SOCS3 peptidomimetics
could be endowed with a therapeutic potential in diseases with activated
inflammatory cytokines.