Saquinavir-NO inhibits S6 kinase activity, impairs secretion of the encephalytogenic cytokines interleukin-17 and interferon-gamma and ameliorates experimental autoimmune encephalomyelitis.

Abstract

NO-hybridization of the HIV protease inhibitor Saquinavir generates a new chemical entity named Saq-NO, that retains the anti-viral activity and exerts lower toxicity. We show that Saq-NO inhibited the generation of various cytokines in ConA-stimulated unfractionated murine spleen cells and rat lymph nodes stimulated with ConA as well as in purified CD4(+) T cells in vitro and reduced the circulating levels of cytokines in mice challenged with anti-CD3 antibody. Furthermore, Saq-NO reduced IL-17 and IFN-γ production in myelin basic protein (MBP)-specific cells isolated from rats immunized with MBP. These findings translated well into the in vivo setting as Saq-NO ameliorated the course of the disease in two preclinical models of multiple sclerosis. Our results demonstrate that Saq-NO exerts immunomodulatory effects that warrant studies on its application in autoimmune diseases.

• Authors: Filip Petković, Jana Blaževski, Miljana Momčilović, Gordana Timotijević, Mai-Britt Zocca, Sanja Mijatović, Danijela Maksimović-Ivanić, Katia Mangano, Paolo Fagone, Stanislava Stošić-Grujičić, Ferdinando Nicoletti, Djordje Miljković
• Journal: Journal of neuroimmunology (J Neuroimmunol) Vol. 259 Issue 1-2 Pg. 55-65 (Jun 15 2013) ISSN: 1872-8421 [Electronic] Netherlands
• PMID: 23602714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• (3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide
• Benzofurans
• CD3 Complex
• Cytokines
• Il17a protein, mouse
• Il17a protein, rat
• Interleukin-17
• Protein Kinase Inhibitors
• Quinolines
• saquinavir-NO
• Interferon-gamma
• Ribosomal Protein S6 Kinases
• Saquinavir

Topics

• Animals
• Benzofurans
• CD3 Complex (metabolism)
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Cells, Cultured
• Cytokines (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology, metabolism)
• Interferon-gamma (metabolism)
• Interleukin-17 (metabolism)
• Lymph Nodes (cytology)
• Mice
• Mice, Inbred BALB C
• Neuroimmunomodulation (drug effects, immunology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Quinolines
• Rats
• Rats, Inbred Strains
• Ribosomal Protein S6 Kinases (antagonists & inhibitors, metabolism)
• Saquinavir (analogs & derivatives, pharmacology)
• Spleen (cytology)