Total Synthesis of Novel Antimicrobial β-Hairpin Capitellacin Via Rapid Flow-Based SPPS Assembly and Regioselective On-Resin Disulfide Cyclisation

Abstract

Antimicrobial resistance is an ever-increasing global health risk that remains one of the World Health Organisations top priorities. Antimicrobial peptides, the host defence molecules of living organisms, are a rapidly developing class of molecules with promise for the treatment of drug resistant infections. We herein describe the first total synthesis of capitellacin, a novel β-hairpin antimicrobial peptide with great therapeutic potential. To the best of our knowledge, this represents the first synthesis of a disulfide-rich peptide employing flow-based solid phase peptide synthesis methodology partnered with a unique all on-resin, fully orthogonal regioselective sequential disulfide formation effected by iodine. We also present important considerations when introducing multiple Cys residues under high temperature typically used in modern and efficient SPPS protocols. By standardising this unique on-resin methodology we expedited our synthesis, avoiding solution phase manipulations or aqueous work-ups. Thus, the optimised methodology is applicable for streamlining syntheses of other bioactive disulfide-rich peptides. Synthetic capitellacin possessed potent activity towards Gram-negative bacteria (MIC 1–4 µM), but minimal activity towards Staphylococcus aureus (MIC > 64 µM).