期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 243, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114781
关键词
Mimetic peptides; Cytokine signaling; JAK/STAT; SOCS1; Cyclic peptides
资金
- Fondazione Italiana Sclerosi Multipla (FISM) [2020/PR-Single/015]
This study aimed to optimize the peptide structure and improve the biological activity of KIR-SOCS1. By utilizing different techniques, the researchers found that the size of the cyclic structure was crucial for its interaction with JAK2, and substituting native residues with un-natural building blocks enhanced the stability and affinity. These findings contribute to increasing the structural knowledge required for the recognition of SOCS1/JAK2 and advancing towards the development of more drug-like compounds.
Suppressors of cytokine signaling 1 (SOCS1) protein, a negative regulator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that mimetics of KIR-SOCS1 can be potent therapeutics in several disorders (e.g., neurological, autoimmune or cardiovascular diseases). In this work, starting from a recently identified cyclic peptidomimetic of KIR-SOCS1, icPS5(Nal1), to optimize the peptide structure and improve its biological activity, we designed novel derivatives, containing crucial amino acids substitutions and/or modifications affecting the ring size. By combining microscale thermophoresis (MST), Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR) and computational studies, we showed that the cycle size plays a key role in the interaction with JAK2 and the substitution of native residues with un-natural building blocks is a valid tool to maintain low-micromolar affinity toward JAK2, greatly increasing their serum stability. These findings contribute to increase the structural knowledge required for the recognition of SOCS1/JAK2 and to progress towards their conversion into more drug-like compounds.
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