Immunological and Toxicological Assessment of Triterpenoid Saponins Bearing Lewis-X- and QS-21-Based Trisaccharides

Marin, Oscar Javier Gamboa; Adda-Bouchard, Yasmine; Sylla, Balla; Verma, Nitish; Charpentier, Tania; Huber, Mmatthew; Lopez, Guillaume; Pichette, Andre; Lamarre, Alain ORCID: https://orcid.org/0000-0002-7913-871X et Gauthier, Charles ORCID: https://orcid.org/0000-0002-2475-2050 (2025). Immunological and Toxicological Assessment of Triterpenoid Saponins Bearing Lewis-X- and QS-21-Based Trisaccharides Chemistry-a European Journal , vol. 31 , nº 28. pp. 1-10. DOI: 10.1002/chem.202500994.

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Résumé

The search for safer and more effective vaccine adjuvants has intensified in recent years, with triterpenoid saponins like QS-21 and its analogues emerging as promising candidates. We report the synthesis of a novel QS-21 analogue featuring betulinic acid as aglycone, a lupane-type triterpenoid with low toxicity derived from white birch bark. Two convergent synthetic routes, involving different protecting groups and glycosyl donors (bromide and trichloroacetimidate), were optimized to construct the QS-21-based linear trisaccharide motif critical for adjuvant activity. This strategy also enabled efficient preparation of the structurally similar echinocystic acid analogue reported by Gin. The immunological and toxicological profiles of these chimeric saponins, along with Lewis-X-containing and rhamnose-modified derivatives, were evaluated in C57BL/6 wild-type and hDC-SIGN transgenic mice. While the synthetic saponins exhibited low toxicity in vitro and in vivo, replacing echinocystic acid with betulinic acid reduced immunogenicity when tested with ovalbumin as a model antigen compared to alhydrogel and QS-21. These findings provide a foundation for developing saponin-based adjuvants and demonstrate the utility of advanced glycosylation strategies for synthesizing complex unnatural triterpenoid saponins.

Type de document:	Article
Informations complémentaires:	document: e202500994 This work was supported in part by funds from a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant (RGPIN-2022–04515, to C.G.), a Fonds de recherche du Québec – Nature et technologies (FRQNT) Team grant (2021- PR-283932, to C.G., A.P., and A.L.), and an NSERC-FRQNT Team Research supplement – Alliance grant (ALLRP 560901–20, to C.G.). C.G. was also supported by a Fonds de recherche du Québec – Santé (FRQS) Research Scholars Senior Career Award. A.L. holds the Jeanne and J.-Louis Lévesque Research Chair in Immunovirology from the J.-Louis Lévesque Foundation. O.J.G.M. thanks FRQNT and the Armand-Frappier Foundation for Ph.D. scholarships
Mots-clés libres:	Immunogenicity; Lewis-x trisaccharide; QS-21 analogues; toxicity; triterpenoid saponins
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	07 juill. 2025 18:53
Dernière modification:	07 juill. 2025 18:53
URI:	https://espace.inrs.ca/id/eprint/16492

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