title: 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.affiliation: Department of Immunology, Institute for Biological Research Siniša Stanković, University of Belgrade, Serbia.
authors.forename: Filip
authors.initials: F
authors.lastname: Petković
authors.forename: Jana
authors.initials: J
authors.lastname: Blaževski
authors.forename: Miljana
authors.initials: M
authors.lastname: Momčilović
authors.forename: Gordana
authors.initials: G
authors.lastname: Timotijević
authors.forename: Mai-Britt
authors.initials: MB
authors.lastname: Zocca
authors.forename: Sanja
authors.initials: S
authors.lastname: Mijatović
authors.forename: Danijela
authors.initials: D
authors.lastname: Maksimović-Ivanić
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Stanislava
authors.initials: S
authors.lastname: Stošić-Grujičić
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Djordje
authors.initials: D
authors.lastname: Miljković
mesh_terms: D000818:Animals; D001572:Benzofurans; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011804:Quinolines; D051381:Rats; D011919:Rats, Inbred Strains; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019258:Saquinavir / Q000031:analogs & derivatives* / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
chemical_list: C576715:(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; D001572:Benzofurans; D017252:CD3 Complex; D016207:Cytokines; C098680:Il17a protein, mouse; C515934:Il17a protein, rat; D020381:Interleukin-17; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C557004:saquinavir-NO; D007371:Interferon-gamma; D019893:Ribosomal Protein S6 Kinases; D019258:Saquinavir