The immune response to vaccines is often enhanced by the presence of adjuvants — compounds that modify the behaviour of other agents while having little direct effect themselves. Few adjuvants that fulfil the requirements of low toxicity and sufficient potency are available for use in vaccines for infectious diseases and cancer. QS-21, a member of the naturally occurring class of compounds known as saponins, has showed promise in numerous clinical trials but there are several limitations associated with its use as an adjuvant. These include difficulty in isolation, dose-limiting toxicity and chemical instability owing to the presence of readily hydrolysable ester linkages. Now, Michelle Adams and co-workers from the Memorial Sloan-Kettering Cancer Centre, New York, have begun to address these issues by developing1 a semi-synthetic approach to QS-21 analogues.

QS-21 is made up of complex carbohydrate and terpene portions and a glycosylated acyl chain. The mechanism by which it promotes immune response is unknown, however, the acyl side-chain is known to be important for its activity. The researchers synthesized three analogues — two of which incorporated simplified acyl side-chains — and replaced the easily hydrolysable ester linkages of QS-21 with more stable amide bonds to overcome the problem of chemical instability. Interestingly, the QS-21 analogues not only showed comparable or better adjuvant activity to QS-21 itself, but also lower toxicity.

This highly convergent synthesis of the analogues takes 30 fewer steps compared with that for QS-21. It also allows the formation of other potent analogues and the possibility of including molecular probes that could enable more elaborate studies into their mechanism of action.