Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis

Thell, Kathrin, Hellinger, Roland, Sahin, Emine, Michenthaler, Paul, Gold-Binder, Markus, Haider, Thomas, Kuttke, Mario, Liutkeviciute, Zita, Goeransson, Ulf, Gruendemann, Carsten, Schabbauer, Gernot and Gruber, Christian W. (2016) Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 113 15: 3960-3965. doi:10.1073/pnas.1519960113


Author Thell, Kathrin
Hellinger, Roland
Sahin, Emine
Michenthaler, Paul
Gold-Binder, Markus
Haider, Thomas
Kuttke, Mario
Liutkeviciute, Zita
Goeransson, Ulf
Gruendemann, Carsten
Schabbauer, Gernot
Gruber, Christian W.
Title Oral activity of a nature-derived cyclic peptide for the treatment of multiple sclerosis
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 1091-6490
0027-8424
Publication date 2016-04-12
Year available 2016
Sub-type Article (original research)
DOI 10.1073/pnas.1519960113
Open Access Status Not yet assessed
Volume 113
Issue 15
Start page 3960
End page 3965
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
Abstract Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. It is characterized by autoreactive 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.
Keyword Cyclic peptides
Drug discovery
Immunopharmacology
Multiple sclerosis
Plant natural product
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID FWF-P24743
P1308423
FT140100730
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Biomedical Sciences Publications
 
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