Quillaja saponin variants with central glycosidic linkage modifications exhibit distinct conformations and adjuvant activities Journal Article


Authors: Walkowicz, W. E.; Fernández-Tejada, A.; George, C.; Corzana, F.; Jiménez-Barbero, J.; Ragupathi, G.; Tan, D. S.; Gin, D. Y.
Article Title: Quillaja saponin 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 QS-21 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 in in vivo adjuvant 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 the Quillaja saponins 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. © The Royal Society of Chemistry 2016.
Keywords: molecular dynamics; toxicity; vaccines; conformations; chemical instability; dose limiting toxicity; metabolites; emulsification; structure activity relationships; conformational preferences; glycosidic linkages; macromolecular targets; structural modifications; therapeutic vaccines
Journal Title: Chemical Science
Volume: 7
Issue: 3
ISSN: 2041-6520
Publisher: Royal Society of Chemistry  
Date Published: 2016-03-01
Start Page: 2371
End Page: 2380
Language: English
DOI: 10.1039/c5sc02978c
PROVIDER: scopus
PMCID: PMC4800320
PUBMED: 27014435
DOI/URL:
Notes: Article -- Export Date: 4 April 2016 -- Source: Scopus
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MSK Authors
  1. Govindaswami Ragupathi
    133 Ragupathi
  2. Derek S Tan
    68 Tan
  3. David Y Gin
    41 Gin
  4. Constantine M George
    10 George