Bacterial lipoproteins and lipopeptides are known to stimulate the innate immune system through TLR2.  The pertinent structural feature for this pathogen associated molecular pattern (PAMP) recognition occurs in the N-terminal amino acid, namely an unique N-acyl-S-diacylglyceryl cysteine motif.  High-throughput cell-based screens for small molecule inducer of cytokine production led to the identification of a series of lipopeptides, which were confirmed to be TLR2 agonists through reporter assays and genetic manipulation.  Chemical modifications were carried out in three regions of the TLR2 pharmacophore: acyl chains, cysteine glycerol core, and peptide portion.  Consistent with the available crystal structure information, two-lipid chain are agonists of TLR2/6, while three-lipid chain are agonist of TLR1/2.  Stereochemistry and linking chemistry are important on the cysteine glycerol core, while the peptide portion can tolerate a wide variety of function groups.  Detailed SAR studies will be described.<br/>

Structural activity relationship of lipopeptide TLR2 agonist

251st National Meeting (2016)

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