A coordinated synthesis and conjugation strategy for the preparation of homogeneous glycoconjugate vaccine candidates.

Glycoconjugates are the center of many therapeutic strategies and carbohydrate-based vaccines in particular hold great promise. The development of glycovaccines, however, can be hindered by the limited access offered by natural sources to homogeneous antigenic carbohydrates; efficient chemical synthesis offers an attractive route to pure samples of these carbohydrates. Furthermore, for an optimal immune response, the carbohydrate antigen should be conjugated to an immunogenic carrier, usually a protein. The synthesis and use of well-defined glycoprotein therapeutics and glycovaccines—uniform in sugar, site, and level of protein attachment—is rare and most constructs are prepared and administered as complex mixtures. 10] Even strategies that utilize pure synthetic glycan may employ non-selective methods for subsequent conjugation to a protein carrier. 7, 11, 12] Given the unknown influence of conjugation site on immunogenic response, it is remarkable that, to our knowledge, no homogeneous glycovaccine has been studied. To fully evaluate the structure–activity relationships (SARs) between glycoprotein and immunogenicity, we have initiated a program for the construction of such “pure” or uniform glycoconjugate vaccines. We report a coherent strategy for homogenous glycoprotein construction that coordinates both carbohydrate synthesis and conjugation methodology. This approach features glycosyl disulfides as versatile donors in complex carbohydrate synthesis, providing strategic access to glycosyl thiols that can be site-specifically attached to a protein carrier through a well-defined thioether linkage (Scheme 1).