Synthesis of Lipopeptides by CLipPA Chemistry.

Lipidation of polypeptides with a fatty acid to form N-linked lipopeptides can be a time consuming process due to the need to mask other reactive function groups present on the side chains of amino acids. Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology enables the direct lipidation of unprotected peptides containing a free thiol group to afford S-lipidated lipopeptides. A generalized procedure for the synthesis of S-lipopeptides is described which facilities rapid preparation of tens of analogs of lipopeptides from a single thiolated polypeptide precursor.

Thiol-ene Enabled Chemical Synthesis of Truncated S-Lipidated Teixobactin Analogs.

Herein is described the introduction of lipid moieties onto a simplified teixobactin pharmacophore using a modified Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technique, whereby cysteine was substituted for 3-mercaptopropionic acid (3-MPA). A truncated teixobactin analog was prepared with the requisite thiol handle, thus enabling an array of vinyl esters to be conveniently conjugated onto the simplified teixobactin pharmacophore to yield S-lipidated cyclic lipopeptides.

Synthesis of Antimicrobial Lipopeptides Using the "CLipPA" Thiol-Ene Reaction.

Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology provides a facile method for the lipidation of unprotected peptides containing a free thiol group by using a "click" radical-initiated thiol-ene reaction to effect addition to a vinyl ester. The methodology is highly versatile, leading to high conversion rates while maintaining excellent chemoselectivity and tolerance for a large variety of peptide substrates and functional groups. Herein we describe the simple general procedure for the synthesis of a focused library of bioactive S-lipidated antimicrobial peptides via late-stage derivatization using solution-phase CLipPA lipidation.