![Synthesis of cyclotides. Cyclotides were assembled as linear precursors using FMOC chemistry, and cyclized using native chemical ligation. (1) Dawson’s resin containing di-Fmoc-3,4-diaminobenzoic acid (Dbz) as linker is the starting point. (2) Couplings are performed using microwave-assisted FMOC synthesis (asterisk marks the first amino acid; the last amino acid is a BOC-protected cysteine). (3) Acylation and activation of the resin bound Dbz-precursor to yield the N-acylurea peptide (Nbz-peptide). (4) Full deprotection and resin cleavage of the Nbz-peptide in one step (Ar, Aryl). Peptide cyclization (5a) via thioesterification, (5b) S, N-intramolecular acyl shift and native chemical ligation and (5c) oxidative folding to yield cyclotides with the native fold. Ribbon representation of a cyclotide (kalata B1, PDB ID code 1NB1) and sequence of [T20K]kalata B1 are shown. Cysteines, disulfide bonds (yellow), and intercysteine loops are indicated.](https://www.pnas.org/content/early/2016/03/22/1519960113/F1.medium.gif)
Synthesis of cyclotides. Cyclotides were assembled as linear precursors using FMOC chemistry, and cyclized using native chemical ligation. (1) Dawson’s resin containing di-Fmoc-3,4-diaminobenzoic acid (Dbz) as linker is the starting point. (2) Couplings are performed using microwave-assisted FMOC synthesis (asterisk marks the first amino acid; the last amino acid is a BOC-protected cysteine). (3) Acylation and activation of the resin bound Dbz-precursor to yield the N-acylurea peptide (Nbz-peptide). (4) Full deprotection and resin cleavage of the Nbz-peptide in one step (Ar, Aryl). Peptide cyclization (5a) via thioesterification, (5b) S, N-intramolecular acyl shift and native chemical ligation and (5c) oxidative folding to yield cyclotides with the native fold. Ribbon representation of a cyclotide (kalata B1, PDB ID code 1NB1) and sequence of [T20K]kalata B1 are shown. Cysteines, disulfide bonds (yellow), and intercysteine loops are indicated.
It is estimated that around 2.5 million people are affected by MS worldwide. The discovery made by the Viennese scientists now offers hope that the disease can be halted at a very early stage or, at the very least, its progression greatly retarded. “As soon as functional neurological problems occur and an MRI scan identifies early pathological changes in the central nervous system, the drug can be given as a basic therapy… It is therefore possible that we could extend the interval between episodes or possibly prevent an onset of the disease,” say Gruber and Schabbauer.
MedUni Vienna, together with Freiburg University Hospital has filed patent applications in several countries and licensed them out to Cyxone, a company they have set up to carry out further development. The aim of this collaboration is to develop a safe, orally active drug for treating multiple sclerosis. A Phase I clinical trial for this could start at the end of 2018, says Gruber.
Cyclotides are macrocyclic plant peptides that can be isolated from all the main plant families (e.g. coffee plants, cucurbits or even grasses and plants of the nightshade family) and therefore represent a large and wide-ranging group of natural substances. A further advantage: the medicine obtained from them can be taken orally. Many of the current MS treatments today have to be administered intravenously.
The mode of action of cyclotides was discovered 3 years ago, at MedUni Vienna, in collaboration with researchers from Freiburg University Hospital: they suppress the messenger substance IL-2 and hence the division of T cells, which act as “killer” or “helper” cells in the human immune system response. Hence, cyclotides could also possibly be used to treat other diseases characterized by an overactive, misdirected immune response, such as rheumatoid arthritis, for example.
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