Adjuvants are the substances added to a vaccine for eliciting and modulating immune response. QS-21 is the most promising candidate that is employed in certain adjuvant formulations, e.g., AS01, but due to its inherent toxicity, there is a need to develop vaccine adjuvant candidates that are less toxic and more potent. The importance of the saccharide motif on the left-wing of the triterpene core and C23-aldehyde in eliciting adjuvant activity of QS-21-derived vaccine adjuvants is a debatable topic. We synthesized novel QS-21 analogues having a disaccharide sugar motif attached to the left side of the triterpene core with varied acyl chain lengths. Our synthesized compounds demonstrate better adjuvant activity as compared to TQL-1055, which indicates that the left-wing sugar motif is important in eliciting adjuvant activity; moreover, our synthesized compounds VA-204 and VA-205 also demonstrate better adjuvant activity as compared to QS-21. We also synthesized QS-21 analogues in which the C23-aldehyde group was replaced with oxime (VA-207), alcohol (VA-208), and carboxylic acid (VA-209) groups; these compounds showed reduced toxicity while retaining the activity, indicating that C23-aldehyde is not imperative and its conversion leads to reduced toxicity. This strategy can be employed to reduce the toxicity associated with QS saponin natural products.
Siddique et al. (Mon,) studied this question.