![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...
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