The development of vaccines to combat vaccine resistant cancers and infectious diseases has relied significantly on constructs employing subunit antigens. While the use of defined molecular antigens offers advantages in terms of safety and precision in immune response targeting, they are typically less immunogenic. Often, these vaccine formulations require an adjuvant, a substance that potentiates immune response. The critical roles of vaccine adjuvants lie in their ability to (1) enable the use of otherwise impotent antigens, (2) extend the benefits of vaccines to poor responders (e.g., older or immune-compromised patients), and (3) effect "dose-sparing" of rare and expensive antigens in short supply (e.g., in an epidemic). The natural product saponin QS-21 is the adjuvant of choice in numerous promising antitumor and antiviral vaccine clinical trials, despite liabilities associated with toxicity, chemical instability, and lack of availability in pure form. This grant application comprises a multi-disciplinary approach toward the chemical synthesis and immunological evaluation of several novel classes of newly discovered saponin adjuvants, including the jujubosides, lablabosides, and soyasaponins.
The Specific Aims of this research program will involve: (1) the total synthesis of jujuboside A and analogs, employing a novel formal ketene-hetero-Diels-Alder reaction;(2) the semisynthesis of lablaboside F and analogs, employing a host of dehydrative, oxidative and imidate glycosylation methodologies developed in our laboratory;(3) the semisynthesis of soyasaponin A1 and analogs, employing novel variants of regio- and stereoselective 20 C-H activation with an aldoxime as the directing group;and (4) preclinical assessment of the synthetic saponin adjuvants, providing data for screening of adjuvant performance for future advancement to clinical trials. These efforts will address fundamental chemical and immunological questions associated with several novel promising saponin adjuvants, and holds the promise of yielding novel therapeutics in the vaccine arena.

Public Health Relevance

The success of antitumor and antiviral vaccines often requires the use of an adjuvant, a substance that is itself not necessarily immunogenic, but significantly enhances the immune response of a patient to a co- administered antigen. This grant application comprises a multi-disciplinary approach toward the preparation, discovery and evaluation of novel adjuvant molecules essential in the development of vaccines for cancer and infectious diseases. These efforts will address fundamental chemical and immunological challenges associated with novel adjuvant discovery, and holds the promise of yielding novel therapeutics in the vaccine arena.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058833-15
Application #
8496063
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Lees, Robert G
Project Start
1999-02-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$543,480
Indirect Cost
$258,787
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fernández-Tejada, Alberto; Tan, Derek S; Gin, David Y (2016) Development of Improved Vaccine Adjuvants Based on the Saponin Natural Product QS-21 through Chemical Synthesis. Acc Chem Res 49:1741-56
Walkowicz, William E; Fernández-Tejada, Alberto; George, Constantine et al. (2016) Quillaja Saponin Variants with Central Glycosidic Linkage Modifications Exhibit Distinct Conformations and Adjuvant Activities. Chem Sci 7:2371-2380
Fernández-Tejada, Alberto; Tan, Derek S; Gin, David Y (2015) Versatile strategy for the divergent synthesis of linear oligosaccharide domain variants of Quillaja saponin vaccine adjuvants. Chem Commun (Camb) 51:13949-52
Fernández-Tejada, Alberto; Chea, Eric K; George, Constantine et al. (2014) Design, synthesis, and immunologic evaluation of vaccine adjuvant conjugates based on QS-21 and tucaresol. Bioorg Med Chem 22:5917-23
Fernández-Tejada, Alberto; Chea, Eric K; George, Constantine et al. (2014) Development of a minimal saponin vaccine adjuvant based on QS-21. Nat Chem 6:635-43
Chea, Eric K; Fernandez-Tejada, Alberto; Damani, Payal et al. (2012) Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes. J Am Chem Soc 134:13448-57
Huh, Jun R; Leung, Monica W L; Huang, Pengxiang et al. (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity. Nature 472:486-90
Ragupathi, Govind; Gardner, Jeffrey R; Livingston, Philip O et al. (2011) Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer. Expert Rev Vaccines 10:463-70
Adams, Michelle M; Damani, Payal; Perl, Nicholas R et al. (2010) Design and synthesis of potent Quillaja saponin vaccine adjuvants. J Am Chem Soc 132:1939-45
Ragupathi, Govind; Damani, Payal; Deng, Kai et al. (2010) Preclinical evaluation of the synthetic adjuvant SQS-21 and its constituent isomeric saponins. Vaccine 28:4260-7

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