Abstract:
Toll-like Receptor 2 (TLR2) is a transmembrane pattern recognition receptor found on the surface of dendritic cells and is involved in the environmental sampling of antigenic material. Recently, this receptor has attracted attention as an upcoming therapeutic target for cancer in the field of immunotherapy. Lipopeptides containing the N-terminal Pam₂Cys amino acid residue are known agonists at the TLR-2 receptor. This thesis reports the probing of the structure-activity relationship of TLR2 with Pam₂Cys containing antigenic peptides and structurally related analogues with the aim of developing new agonists for self-adjuvanting vaccines against cancer. Modifications to the Pam₂Cys structure including homologation between the two fatty acid esters, replacement of either of the esters with ethers, and variation of stereochemistry at the C-6 stereocenter. These building blocks were then conjugated to a peptide antigen using Fmoc solid phase peptide synthesis to give a series of lipidated peptide antigens which were then in turn evaluated for their ability to stimulate TLR2 activity.
