Synthesis and Evaluation of Novel TLR2 Agonists as Potential Adjuvants for Cancer Vaccines

Cancer immunotherapy
has gained increasing attention due to its
potential specificity and lack of adverse side effects when compared
to more traditional modes of treatment. Toll-like receptor 2 (TLR2)
agonists are lipopeptides possessing the S-[2,3-bis­(palmitoyloxy)­propyl]-l-cysteine (Pam2Cys) motif and exhibit potent immunostimulatory
effects. These agonists offer a means of providing “danger
signals” in order to activate the immune system toward tumor
antigens. Thus, the development of TLR2 agonists is attractive in
the search of potential immunostimulants for cancer. Existing SAR
studies of Pam2Cys with TLR2 indicate that the structural
requirements for activity are, for the most part, very intolerable.
We have investigated the importance of stereochemistry, the effect
of N-terminal acylation, and homologation between
the two ester functionalities in Pam2Cys-conjugated lipopeptides
on TLR2 activity. The R diastereomer is significantly
more potent than the S diastereomer and N-terminal modification generally lowers TLR2 activity. Most notably,
homologation gives rise to analogues which are comparatively active
to the native Pam2Cys containing constructs.