Concomitant Effect of Left-Wing Disaccharide, Chain Length, and Modification of C23-Aldehyde: An Effort to Develop Simple and Effective QS-21 Derivative Vaccine Adjuvants and Exploration of the Structural–Activity Relationship

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.