Plant-based production of an orally active cyclotide for the treatment of multiple sclerosis

• DOI: 10.1007/s11248-023-00341-1
• Publication Date: 2023-03-17T09:02:45Z
• Authors: Mark A. Jackson; Jing Xie; Linh T. T. Nguyen; Xiaohan Wang; Kuok Yap; Peta J. Harvey; Edward K. Gilding; David J. Craik
• Keywords: Cyclic peptide

Multiple sclerosis (MS) is a debilitating disease that requires prolonged treatment with often severe side effects. One experimental MS therapeutic currently under development single amino acid mutant of plant peptide termed kalata B1, the cyclotide family. Like all cyclotides, candidate [T20K]kB1 highly stable as it contains cyclic backbone cross-linked by three disulfide bonds in knot-like structure. This stability much sought after for drugs, which despite exquisite selectivity their targets, are prone to rapid degradation human serum. In preliminary investigations, was found retains oral activity autoimmune encephalomyelitis, model mice, thus opening up opportunities dosing peptide. Although can be synthetically produced, recombinant production system provides advantages, specifically reduced scale-up costs and reductions chemical waste. this study, we demonstrate capacity Australian native Nicotiana benthamiana produce structurally identical synthetic By optimizing co-expressed cyclizing enzyme, precursor arrangements, transgene regulatory regions, yield crude extracts ~ 0.3 mg/g dry mass) whole plants close 1.0 mass isolated infiltrated leaves. With large-scale facilities coming on-line across world, sustainable cost-effective cyclotide-based therapeutics now within reach.