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

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

doi:10.1016/j.jneuroim.2013.03.010

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

J Neuroimmunol. 2013 Jun 15;259(1-2):55-65. doi: 10.1016/j.jneuroim.2013.03.010. Epub 2013 Apr 18.

Authors

Filip Petković¹, 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

Affiliation

¹ Department of Immunology, Institute for Biological Research Siniša Stanković, University of Belgrade, Serbia.

PMID: 23602714
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzofurans
CD3 Complex / metabolism
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / metabolism
Cells, Cultured
Cytokines / metabolism*
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
Neuroimmunomodulation / drug effects
Neuroimmunomodulation / immunology
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

Substances

(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