Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 15, Pages 3960-3965Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1519960113
Keywords
cyclic peptides; multiple sclerosis; immunopharmacology; plant natural product; drug discovery
Categories
Funding
- Austrian Science Fund [FWF-P24743]
- Austria Wirtschaftsservice GmbH Prize [P1308423]
- Australian Research Council [FT140100730]
- Software AG Foundation
- DAMUS-DONATA e.V.
- Austrian Science Fund (FWF) [P 24743] Funding Source: researchfish
- Austrian Science Fund (FWF) [P24743] Funding Source: Austrian Science Fund (FWF)
- Australian Research Council [FT140100730] Funding Source: Australian Research Council
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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.
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