Head‐to‐Tail Cyclized Cystine‐Knot Peptides by a Combined Recombinant and Chemical Route of Synthesis

Backbone cyclization of recombinantly produced cystine knot peptides, resulting in correctly folded macrocyclic disulfide‐bridged peptides, is reported. It does not require protecting groups, takes place in aqueous solution, and is devoid of racemization and solubility problems. Scaling up to production of multimilligram amounts of iminocyclotides seems feasible. The resulting iminocyclotides are biologically active proteinase inhibitors—imino‐cyclo‐McoEeTI KKV was identified as the most potent proteinaceous inhibitor of human mast cell tryptase known.