Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1: Progress toward novel anti-inflammatory therapeutics(272 views) La Manna S, Lopez-sanz L, Bernal S, Fortuna S, Mercurio FA, Leone M, Gomez-guerrero C, Marasco D
Eur J Med Chem (ISSN: 0223-5234linking, 1768-3254, 1768-3254electronic), 2021 Oct 5; 221: 113547-113547.
Keywords: Cytokine Signaling, Inflammation, Jak Stat, Mimetic Peptides, Oxidative Stress, Socs1, Animals
, Anti-Inflammatory Agents Chemical Synthesis Chemistry Pharmacology
, Cells, Cultured
, Dose-Response Relationship, Drug
, Molecular Structure
, Peptidomimetics Chemical Synthesis Chemistry Pharmacology
, Protein Kinase Inhibitors Chemical Synthesis Chemistry Pharmacology
, Structure-Activity Relationship
, Suppressor Of Cytokine Signaling 1 Protein Antagonists, Inhibitors Metabolism,
Affiliations: *** IBB - CNR ***
Department of Pharmacy - University of Naples "Federico II", 80134, Naples, Italy
Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040, Madrid, Spain.
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040, Madrid, Spain.
Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34127, Trieste, Italy.
Institute of Biostructures and Bioimaging - CNR, 80134, Naples, Italy.
References: Not available.
Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1: Progress toward novel anti-inflammatory therapeutics
Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs.
Cyclic mimetics of kinase-inhibitory region of Suppressors of Cytokine Signaling 1: Progress toward novel anti-inflammatory therapeutics
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123 Records (113 excluding Abstracts). Total impact factor: 500.436 (464.255 excluding Abstracts). Total 5 year impact factor: 442.761 (405.909 excluding Abstracts).