title: Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis.
abstract: Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by auto-reactive T cells that induce demyelination and neuronal degradation. Treatment options are still limited and several MS medications need to be administered by parenteral application but are modestly effective. Oral active drugs such as fingolimod have been weighed down by safety concerns. Consequently, there is a demand for novel, especially orally active therapeutics. Nature offers an abundance of compounds for drug discovery. Recently, the circular plant peptide kalata B1 was shown to silence T-cell proliferation in vitro in an IL-2-dependent mechanism. Owing to this promising effect, we aimed to determine in vivo activity of the cyclotide [T20K]kalata B1 using the MS mouse model experimental autoimmune encephalomyelitis (EAE). Treatment of mice with the cyclotide resulted in a significant delay and diminished symptoms of EAE by oral administration. Cyclotide application substantially impeded disease progression and did not exhibit adverse effects. Inhibition of lymphocyte proliferation and the reduction of proinflammatory cytokines, in particular IL-2, distinguish the cyclotide from other marketed drugs. Considering their stable structural topology and oral activity, cyclotides are candidates as peptide therapeutics for pharmaceutical drug development for treatment of T-cell-mediated disorders.
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thell
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Roland
authors.initials: R
authors.lastname: Hellinger
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Paul
authors.initials: P
authors.lastname: Michenthaler
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Markus
authors.initials: M
authors.lastname: Gold-Binder
authors.affiliation: University Clinic for Trauma Surgery, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Thomas
authors.initials: T
authors.lastname: Haider
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Mario
authors.initials: M
authors.lastname: Kuttke
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: Zita
authors.initials: Z
authors.lastname: Liutkevičiūtė
authors.affiliation: Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden;
authors.forename: Ulf
authors.initials: U
authors.lastname: Göransson
authors.affiliation: Center for Complementary Medicine, Department of Environmental Health Sciences and Hospital Infection Control, Medical Center-University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Gründemann
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; gernot.schabbauer@meduniwien.ac.at christian.w.gruber@meduniwien.ac.at.
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.affiliation: Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia; gernot.schabbauer@meduniwien.ac.at christian.w.gruber@meduniwien.ac.at.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Gruber
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D047169:Cyclotides / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D047169:Cyclotides; D016207:Cytokines; D007376:Interleukin-2; C091930:kalata B1
keywords: cyclic peptides; drug discovery; immunopharmacology; multiple sclerosis; plant natural product