title: QuillajaSaponin Variants with Central Glycosidic Linkage Modifications Exhibit Distinct Conformations and Adjuvant Activities.
abstract: Immunological adjuvants such as the saponin natural product QS-21 help stimulate the immune response to co-administered antigens and have become increasingly important in the development of prophylactic and therapeutic vaccines. However, clinical use of QS21 is encumbered by chemical instability, dose-limiting toxicity, and low-yielding purification from the natural source. Previous studies of structure-activity relationships in the four structural domains of QS-21 have led to simplified, chemically stable variants that retain potent adjuvant activity and low toxicity in mouse vaccination models. However, modification of the central glycosyl ester linkage has not yet been explored. Herein, we describe the design, synthesis, immunologic evaluation, and molecular dynamics analysis of a series of novel QS-21 variants with different linker lengths, stereochemistry, and flexibility to investigate the role of this linkage in saponin adjuvant activity and conformation. Despite relatively conservative structural modifications, these variants exhibit striking differences inin vivoadjuvant activity that correlate with specific conformational preferences. These results highlight the junction of the triterpene and linear oligosaccharide domains as playing a critical role in the immunoadjuvant activity of theQuillajasaponins and also suggest a mechanism of action involving interaction with a discrete macromolecular target, in contrast to the non-specific mechanisms of emulsion-based adjuvants.
authors.affiliation: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: William E
authors.initials: WE
authors.lastname: Walkowicz
authors.affiliation: Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Chemical & Physical Biology, Center for Biological Research, CIB-CSIC, 28040 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernández-Tejada
authors.affiliation: Melanoma & Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Constantine
authors.initials: C
authors.lastname: George
authors.affiliation: Department of Chemistry, University of La Rioja, 26006 Logroño, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Corzana
authors.affiliation: Chemical & Physical Biology, Center for Biological Research, CIB-CSIC, 28040 Madrid, Spain; Structural Biology, Center for Cooperative Research, CIC-bioGUNE, 48160 Derio-Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.affiliation: Melanoma & Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.affiliation: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, 1275 York Avenue, New York, NY 10065, United States; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
authors.affiliation: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, 1275 York Avenue, New York, NY 10065, United States; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States; Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin