title: Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes.
abstract: QS-21 is a potent immunostimulatory saponin that is currently under clinical investigation as an adjuvant in various vaccines to treat infectious diseases, cancers, and cognitive disorders. Herein, we report the design, synthesis, and preclinical evaluation of simplified QS-21 congeners to define key structural features that are critical for adjuvant activity. Truncation of the linear tetrasaccharide domain revealed that a trisaccharide variant is equipotent to QS-21, while the corresponding disaccharide and monosaccharide congeners are more toxic and less potent, respectively. Modification of the acyl chain domain in the trisaccharide series revealed that a terminal carboxylic acid is well-tolerated while a terminal amine results in reduced adjuvant activity. Acylation of the terminal amine can, in some cases, restore adjuvant activity and enables the synthesis of fluorescently labeled QS-21 variants. Cellular studies with these probes revealed that, contrary to conventional wisdom, the most highly adjuvant active of these fluorescently labeled saponins does not simply associate with the plasma membrane, but rather is internalized by dendritic cells.
authors.affiliation: Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
authors.forename: Eric K
authors.initials: EK
authors.lastname: Chea
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Tejada
authors.forename: Payal
authors.initials: P
authors.lastname: Damani
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Adams
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gardner
authors.forename: Philip O
authors.initials: PO
authors.lastname: Livingston
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin
mesh_terms: D000215:Acylation; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D012503:Saponins / Q000737:chemistry*
chemical_list: D000276:Adjuvants, Immunologic; D012503:Saponins; C078785:saponin QA-21V1