Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes Journal Article

Authors: Chea, E. K.; Fernandez- Tejada, A.; Damani, P.; Adams, M. M.; Gardner, J. R.; Livingston, P. O.; Ragupathi, G.; Gin, D. Y.
Article 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. © 2012 American Chemical Society.
Keywords: controlled study; drug activity; nonhuman; animal cell; mouse; animals; mice; dendritic cell; fluorescence; drug potency; drug screening; drug design; drug synthesis; mice, inbred c57bl; dendritic cells; amine; cell membrane; cell membranes; probes; glucose; molecular structure; adjuvants, immunologic; vaccine; acyl chain; internalization; vaccines; tetrasaccharides; carboxylic acids; tetrasaccharide; saponins; carboxylic acid; clinical investigation; acylation; qs 21; infectious disease; organic compounds; metabolites; mechanical probe; monosaccharide; trisaccharide; mechanistic probes; structural feature; disaccharide
Journal Title: Journal of the American Chemical Society
Volume: 134
Issue: 32
ISSN: 0002-7863
Publisher: American Chemical Society  
Date Published: 2012-08-15
Start Page: 13448
End Page: 13457
Language: English
DOI: 10.1021/ja305121q
PROVIDER: scopus
PUBMED: 22866694
PMCID: PMC3436428
Notes: --- - "Export Date: 4 September 2012" - "CODEN: JACSA" - "Source: Scopus"
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MSK Authors
  1. Govindaswami Ragupathi
    133 Ragupathi
  2. David Y Gin
    41 Gin
  3. Jeffrey Gardner
    33 Gardner
  4. Payal Damani
    9 Damani
  5. Michelle M Adams
    6 Adams
  6. Eric   Chea
    3 Chea