Fmoc-SPPS based synthesis of bioactive cyclic peptides via N-acylurea intermediates

• The plant cyclotides form the largest family of cyclic peptides(1). They contain a signature motif referred to as the cyclic cystine knot, which is derived from the cyclic backbone and three inter-knotted disulfide bonds. Intriguingly, cyclotides can be boiled, treated with chemicals or enzymes without disrupting their overall fold. Thus, they are sometimes labeled as ultra-stable proteins. In addition, cyclotides are tolerant to mutations, and as a scaffold they can successfully accommodate foreign bioactive epitopes of variable sequences(2). Cyclotides share many of these properties with another disulfide containing cyclic plant peptide, the sunflower trypsin inhibitor 1 (SFTI-1)(3). Emerging evidence indicates that cyclotides and SFTI-1 are valuable not only as peptide stabilizing scaffolds; in combination with their cell penetrating properties, these disulfide rich cyclic peptides have significance as intracellular drug carriers. Although both peptides are genetically encoded, studies to ascertain the exact mechanisms of their biosynthesis are currently on going. Thus, the synthesis of cyclotides and SFTI-1 are currently restricted to chemical means. We have recently adapted a Fmoc-SPPS method for cyclic peptide synthesis, via N-acylurea intermediates with the assistance of microwave irradiation.This method is a safe and convenient alternative to Boc-SPPS and has the ability to be automated conveniently. Using this method, parent scaffolds as well as several cyclotide and SFTI-1 analogues with potential antimicrobial and matrix metalloprotease activities were synthesized. With the rising interest in the cyclization concept as a tool to impart stability on unstable peptides, the cyclic peptide synthesis method adapted herein is anticipated to have numerous applications.1. Burman, R.; Gunasekera, S.; Stromstedt, A.; Rosengren, J.; Goransson, U. J. Biol. Chem. 2012 (in press)2. Gunasekera, S.; Foley, F. M.; Clark, R. J.; Sando, L.; Fabri, L. J.; Craik, D. J.; Daly, N. L. J. Med. Chem. 2008, 51, 7697.3. Chan, L. Y.; Gunasekera, S.; Henriques, S. T.; Worth, N. F.; Le, S. J.; Clark, R. J.; Campbell, J. H.; Craik, D. J.; Daly, N. L. Blood 2011, 118, 6709.

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