Circular versions of peptides with medicinal applications often exhibit improved biological activities and stability in comparison to their linear counterparts, but their synthesis can be costly, lengthy and complicated.? Our group has developed a facile route for cyclising peptides using novel reactions based around native chemical ligation (NCL)1NCL joins peptide fragments easily and under mild conditions when one contains a C-terminal thioester and the other an N-terminal free thiol (e.g. as cysteine). Using our chemistry, the required but otherwise problematic production of peptidyl thioesters is circumvented by adapting conditions for the in situ generation of intermediates that can be 'captured' with thiol additives � fragments terminating in Xaa�Cys (where Xaa = Gly, His or Cys) initially undergo retro�NCL to produce C�terminal thioesters. Thus a facile route to circularisation can be applied to linear peptides featuring cysteine at both their N� and C�termini (Figure 1).?1?By applying our chemistry to several therapeutically interesting peptides we are investigating the mechanism, having produced unnatural amino acids, introduced various thiol additives and adjusted pH, and have demonstrated analogues of sunflower�trypsin inhibitor�1 inhibit kallikrein 5, an enzyme indicated in atopic dermatitis disease states like Netherton syndrome.21 Kang et al, Org Biomol Chem, 2009, 7 , 4918�49232 Jiang et al, J Biol Chem, 2011, 286  , 9127�9135

Retro�native chemical ligation rings in the changes for therapeutic peptides

248th National Meeting (2014)

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