Synthesis of Chemically Defined Macromolecules as Vaccine Candidates
Early studies from our lab indicated that HIV has an affinity for surfaces functionalized with beta-galactosyl ceramide (beta-GalCer) and we prepared and characterized functionalized nanoparticles as possible decoys for the virus. As chemists, we became frustrated with our inability to chemically define these nanoparticles with the precision required to implement rational design changes, so we turned our attention to making smaller peptide-based macromolecules. Moving in this direction has led to productive industrial partnerships. Our joint efforts are directed toward the development of peptide-based HIV vaccines and center on the synthesis of chemically defined trivalent displays of immunogenic peptides that were shown to bind to neutralizing antibodies using phage display. We have developed highly efficient synthetic methods for making the peptides and attaching them to a central core structure that supports multivalency. These antiviral vaccine studies have informed our cancer research. Polysialic acid is a cell-surface glycoconjugate that is primarily expressed in cancer cells in adults and its expression is correlated with the spread of cancer. Wishing to mimic an antigenic conformation of polysialic acid, we designed and synthesized amide-linked heteroligomers of sialic acid and glutamic acid. All possible conformations of alternating constructs were prepared and structurally characterized. One construct showed remarkable similarity to an immunogenic conformational epitope of polysialic acid. Studies are continuing toward determining the immunogenic profile of this lead and related molecules.
a. Conboy, J.C., K.D. McReynolds, J. Gervay-Hague, and S.S. Saavedra. Quantitative Measurements of Recombinant HIV Surface Glycoprotein Gp120 Binding to Glycosphingolipids Expressed in Planar Supported Lipid Bilayers. J. Am. Chem. Soc. 2002, 124: 968-977. DOI: 10.1021/ja011225s
b. Saludes, J.P., J.B. Ames, J. Gervay-Hague. Synthesis and structural characterization of sialic acid-glutamic acid hybrid foldamers as conformational surrogates of alpha-2,8-linked polysialic acid. Journal of the American Chemical Society. 2009, 131(15): 5495-505. DOI: 10.1021/ja808286x
c. Schellinger, J.G., L.M. Danan-Leon, J.A. Hoch, A. Kassa, I. Srivastava, D. Davis, J. Gervay-Hague. Synthesis of a trimeric gp120 epitope mimic conjugated to a T-helper peptide to improve antigenicity. Journal of the American Chemical Society. 2011, 133(10): 3230-3. DOI: 10.1021/ja1083915
d. Hsieh, Hsiao-Wu; Schombs, Matthew W.; Gervay-Hague, Jacquelyn. Integrating ReSET with Glycosyl Iodide Glycosylation in Step- Economy Syntheses of Tumor-Associated Carbohydrate Antigens and Immunogenic Glycolipids. Journal of Organic Chemistry. 2014, 79(4): 1736-1748. DOI: 10.1021/jo402736g
e. Hsieh, Hsiao-Wu; Davis, Ryan A.; Hoch, Jessica A.; Gervay-Hague, Jacquelyn. Two-Step Functionalization of Oligosaccharides Using Glycosyl Iodide and Trimethylene Oxide and Its Applications to Multivalent Glycoconjugates. Chemistry – A European Journal. 2014, 20(21): 6444-6454. DOI: 10.1002/chem.201400024