Oral activity of a nature derived cyclic peptide for the treatment of multiple sclerosis
Significance Multiple sclerosis (MS) imposes substantial economic burdens on patients, their families, and society. Until now, there are few therapies available, but often unattractive parenteral application or severe side effects are serious issues. This study highlights the use of circular peptides as orally active T cell specific immunosuppressive therapeutics against the MS model experimental autoimmune encephalomyelitis, without inducing major adverse effects. Our work provides a proof of principle that nature derived cyclic peptides serve as oral active therapeutics, utilizing their intrinsic bioactivity and stable three dimensional structure. Cyclotides are considered a combinatorial peptide library and they can be anticipated to complement the existing collections of natural products that are used in drug discovery. 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.
Proceedings of the National Academy of Sciences