A convenient solid-phase strategy for the synthesis of antimicrobial cyclic lipopeptides

Abstract

A concise solid-phase synthesis of cyclic lipopeptides derived from the antimicrobial peptide c(Lys-Lys-Leu-Lys-Lys-Phe-Lys-Lys-Leu-Gln) (BPC194) was accomplished. Three different synthetic routes were explored. Best results were obtained using a protocol that includes as key steps: (i) synthesis of the cyclic peptidyl resin incorporating the Lys residue to be acylated protected at the N^ε-amino group with an ivDde group, (ii) selective removal of the ivDde group, and (iii) acylation. These compounds were screened for their in vitro growth inhibition of bacterial and fungal phytopathogens and for their cytotoxic effects on eukaryotic cells. A sequence with high antimicrobial activity and low hemolysis was identified, constituting a good candidate for the design of new antimicrobial agents.