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Chemical and Biological Production of Disulfide Rich Backbone-cyclized Peptides
Cyclic peptides can be produced chemically by using solid-phase peptide synthesis, enzymatic chemistry, or expressed in microorganisms using DNA recombinant techniques.
Chemical synthesis of backbone-cyclized peptides
Cyclic peptides ranging from approximately 15-40 amino acids long can be readily synthesized using solid-phase peptide synthesis (SPPS). It involves two steps process: production of linear precursor and cyclization.
Linear precursor α-thioester peptides can be produced by both Boc-based and Fmoc-based chemistry. The most commonly used approach for the production of α-thioester linear cyclotide precursors is using the 3-mercaptopropionamide linker (Boc-based), sulfonamide linker and 3,4-Diaminobenzoic (Dbz) linker (Fmoc-based).
The most commonly used method for the backbone cyclization of the linear cyclotide precursor employs an intramolecular NCL, in which the peptide sequence contains an N-terminal cysteine and an α-thioester group at the C-terminus (Fig. 1A).
Cyclization can be formed by direct chemical coupling of the Nα-amino and C-terminal carboxylic groups using uronium salts as coupling reagent.
Also enzymes such as proteases and trans-peptidases can be used for the production of backbone cyclized polypeptides.
 Li Y, Bi T, Camarero JA, Chemical and biological production of cyclotides. Nature. Adv Bot Res. 2015;76:271-303.
 Camarero JA, Mitchell AR, Synthesis of proteins by native chemical ligation using Fmoc-based chemistry, Protein Pept Lett. 2005 Nov;12(8):723-8.
 Jagadish K, Camarero JA, Recombinant Expression of Cyclotides Using Split Inteins, Methods Mol Biol. 2017;1495:41-55.