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Synthesis of QS-21-based immunoadjuvants.

ABSTRACT: Three structurally defined QS-21-based immune adjuvant candidates (2a-2c) have been synthesized. Application of the two-stage activation glycosylation approach utilizing allyl glycoside building blocks improved the synthetic accessibility of the new adjuvants. The efficient synthesis and establishment of the stand-alone adjuvanticity of the examined synthetic adjuvant (2b) open the door to the pursuit of a new series of structurally defined QS-saponin-based synthetic adjuvants.

SUBMITTER: Wang P

PROVIDER: S-EPMC3937867 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Synthesis of QS-21-based immunoadjuvants.

Wang Pengfei P Dai Qipu Q Thogaripally Punith P Zhang Ping P Michalek Suzanne M SM

The Journal of organic chemistry 20131105 22

Three structurally defined QS-21-based immune adjuvant candidates (2a-2c) have been synthesized. Application of the two-stage activation glycosylation approach utilizing allyl glycoside building blocks improved the synthetic accessibility of the new adjuvants. The efficient synthesis and establishment of the stand-alone adjuvanticity of the examined synthetic adjuvant (2b) open the door to the pursuit of a new series of structurally defined QS-saponin-based synthetic adjuvants. ...[more]

PMID: 24147602

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Development of a minimal saponin vaccine adjuvant based on QS-21.

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Project description: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.

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Complete biosynthesis of the potent vaccine adjuvant QS-21.

Project description:QS-21 is a potent vaccine adjuvant currently sourced by extraction from the Chilean soapbark tree. It is a key component of human vaccines for shingles, malaria, coronavirus disease 2019 and others under development. The structure of QS-21 consists of a glycosylated triterpene scaffold coupled to a complex glycosylated 18-carbon acyl chain that is critical for immunostimulant activity. We previously identified the early pathway steps needed to make the triterpene glycoside scaffold; however, the biosynthetic route to the acyl chain, which is needed for stimulation of T cell proliferation, was unknown. Here, we report the biogenic origin of the acyl chain, characterize the series of enzymes required for its synthesis and addition and reconstitute the entire 20-step pathway in tobacco, thereby demonstrating the production of QS-21 in a heterologous expression system. This advance opens up unprecedented opportunities for bioengineering of vaccine adjuvants, investigating structure-activity relationships and understanding the mechanisms by which these compounds promote the human immune response.

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Project description:We have synthesized a QS-17/18 analogue (7) and evaluated its adjuvant activity in the formulation with rHagB antigen. Compound 7 and QS-21 analogues 5 and 6 are presumably the major components of GPI-0100, a widely used complex mixture of semisynthetic derivatives of Quillaja saponaria (QS) Molina saponins. The QS-17/18 analogue 7 shows an adjuvant activity profile similar to that of GPI-0100, potentiating mixed Th-1/Th-2 immune responses, which is different from those of QS-21 analogues 5 and 6 that probably only induce a Th2-like immunity. The combination of QS-17/18 and QS-21 analogues does not show a synergistic effect. These results suggest that QS-17/18 analogue 7 might be the active component of GPI-0100 responsible for its immunostimulant property. Therefore, compound 7 can not only be a structurally defined alternative to GPI-0100 but also provide a valuable clue for rational design of new QS-based vaccine adjuvants with better adjuvant properties.

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Synthesis and Evaluation of a Self-Adjuvanting Pseudomonal Vaccine Based on Major Outer Membrane Porin OprF Epitopes Formulated with Low-Toxicity QS-21-Containing Liposomes.

Project description:Pseudomonas aeruginosa (PA) is a Gram-negative pathogen that the World Health Organization has ranked as a priority 1 (critical) threat. One potential prophylactic approach to preventing or reducing the incidence of PA would be development of a long sought-after vaccine. Both antibody and CD4+ T-cell responses have been noted as playing key roles in protection against infection. In these studies, we have designed a prototype vaccine consisting of several known linear B-cell epitopes derived from an outer membrane porin F (OprF). The resulting thiol-containing protein was conjugated to a version of the lipopeptide-based Toll-like receptor agonist Pam3CysSK4Mal (10) containing a maleimide moiety and formulated into dipalmitoylphosphatidylcholine (DPPC)/cholesterol (Chol) liposomes. Mice immunized with the resulting vaccine generated antibodies that bound PA14 (serotype O10) in vitro and induced opsonization in the presence of rabbit complement and murine macrophage RAW264.7 cells. The liposome was optimized to contain 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG), Chol, Pam3CysSK4-OprF (12) and the Quillaja saponaria-derived saponin adjuvant QS-21. The resulting vaccine formulation produced significantly higher antibody titers, increased the IgG2a antibody isotype, and increased the number of IgG-producing B-cells as well as splenic primed T-cells. In summary, the liposomal vaccine platform was found highly useful for the generation of a robust and balanced TH1/TH2 response.

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