2. | Fully Synthetic Carbohydrate Tropical Disease Vaccines |
Unique cell surface carbohydrates act as biological markers for a number of particular cell types. Specific carbohydrate structures are found on cells of protozoan parasites such as Leishmania and were observed as the malaria toxin. These antigens may be used to induce a specific immune response that prevents infection. |
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Based on the findings by our collaborators regarding a tentative structure of the malaria toxin responsible for the morbidity and mortality associated with malaria we undertook the total synthesis of the proposed compound. The synthetic material proved highly immunogenic in mice when conjugated to a carrier protein and the antibodies produced in response to the synthetic constructs bound the natural toxin. Our synthetic compound was able to prevent infection and funtcion as a malaria vaccine. Preclinical trials are currently ongoing. Schofield, L.; Hewitt, M.C.; Evans, K.; Siomos, M.A.; Seeberger, P.H.; Synthetic Glycosylphosphatidylinositol of Malaria as a Candidate Anti-toxic Vaccine; Nature, 2002, in press. |
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We also accomplished the linear synthesis of a unique tetrasaccharide antigen found on the Leishmania lipophosphoglycan in solution and on solid support. Glycosyl phosphates proved most successful in this endeavor and allowed for the automated solid-phase synthesis of the target molecule. The synthetic cap tetrasaccharide was conjugated to the immunostimulator lipopeptide Pam3Cys to create a fully synthetic carbohydrate vaccine and to the carrier protein KLH to form a semi-synthetic vaccine.1 The initial immunological evaluations of both constructs are very encouraging as strong B cell and T cell responses were elicited. Hewitt, M.C.; Seeberger P.H.; Automated Solid-Phase Synthesis of the Leishmania Cap Tetrasaccharide; Organic Letters 2001, 3, 3699-3702. Hewitt, M.C.; Seeberger, P.H. Solution and Solid Support Synthesis of a Potential Leishmaniasis Carbohydrate Vaccine., J. Org. Chem. 2001, 66, 4233-4243.
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