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.

Direct synthesis of cyclic lipopeptides using intramolecular native chemical ligation and thiol-ene CLipPA chemistry.

Naturally occurring cyclic lipopeptides exhibit a diverse range of biological activities and possess several favourable properties. Chemically synthesising and modifying these natural compounds can alter their biological and physical properties. Cyclic lipopeptides are often difficult to synthesise, especially when the lipid moiety is directly attached to the cyclic scaffold. The construction of a series of cyclic lipopeptide analogues of the antifungal peptide iturin A is reported herein. The synthesis of the parent peptide macrocycle was achieved using native chemical ligation (NCL), whereupon the regenerated free thiol was used to attach a lipid moiety using Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology.

"CLipP"ing on lipids to generate antibacterial lipopeptides.

We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel "CLipP"ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.

Synthesis and biological evaluation of analogues of the potent ADAM8 inhibitor cyclo(RLsKDK) for the treatment of inflammatory diseases and cancer metastasis.

The metalloproteinase ADAM8 serves as a pivotal catalyst in the development of inflammatory diseases and cancer metastasis. The cyclic peptide cyclo(RLsKDK) has been shown to inhibit the enzymatic activity of ADAM8 with high specificity and potency. Herein we report a structure-activity relationship (SAR) study of cyclo(RLsKDK) that involves the synthesis and biological evaluation of the lead compound and structural analogues thereof. This study provides insight into the ligand-receptor interactions that govern the binding of cyclo(RLsKDK) to the ADAM8 disintegrin domain and represents a stepping stone for the development of new treatments for inflammatory diseases and cancer metastasis.