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

• Published in: Journal of neuroimmunology 2013-06, Vol.259 (1), p.55-65
• Main Authors: Petković, Filip, Blaževski, Jana, Momčilović, Miljana, Timotijević, Gordana, Zocca, Mai-Britt, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Mangano, Katia, Fagone, Paolo, Stošić-Grujičić, Stanislava, Nicoletti, Ferdinando, Miljković, Djordje
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Autoimmunity; Benzofurans; CD3 Complex - metabolism; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cells, Cultured; Cytokines; Cytokines - metabolism; EAE; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Interferon-gamma - metabolism; Interleukin-17 - metabolism; Lymph Nodes - cytology; Mice; Mice, Inbred BALB C; Multiple sclerosis; Neuroimmunomodulation - drug effects; Neuroimmunomodulation - immunology; Neurology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Quinolines; Rats; Rats, Inbred Strains; Ribosomal Protein S6 Kinases - antagonists & inhibitors; Ribosomal Protein S6 Kinases - metabolism; Saquinavir - analogs & derivatives; Saquinavir - pharmacology; Spleen - cytology; T cell
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2013.03.010

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.