INHIBITION OF COMPLEX CARBOHYDRATE BIOSYNTHESIS

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Cell-surface carbohydrates play key roles in many important biological phenomena, e.g. cell-cell recognition, cell-cell adhesion, cell-matrix adhesion, lymphocyte trafficking, and inflation. Understanding the enzymes which process important glycosidic bonds in complex carbohydrates, glycoproteins, and glycolipids has become a central goal of glycochemistry in basic research and medicine. Drugs based on these targets will also be useful in treating diabetes, metastatic cancer and lysosomal storage diseases; some may display potent antiviral and antitumor properties as well. This renewal proposal outlines four specific objectives for study. (l) The synthesis of nagstatin (and other N-acetyl-D-glucosaminidase inhibitors) can lead to new contraceptives, and limit tumor cell metastasis. Other heterocyclic "glycomimetics" (for example, specific inhibitors of glucosidase II) could be of value in elucidating the role of calnexin (a chaperonin) in protein folding. Several new heterocyclic glycosidase inhibitors have been designed to resemble the conformationally flattened transition state of glucoside hydrolysis. (2) Galactosphingolipids have been implicated in an alternative pathway for HIV-1 infection in CD4-negative cells. By using galactosylceramide analogs to map glycolipid binding to the native HIV coat protein gpl20 and its fragments, prospective new strategies for antiviral therapy will be developed. In related work, inhibitors of glucosylceramide synthase will be synthesized to elucidate the metabolic roles of sphingolipids in cancer malignancy, tumor growth and metastasis. (3) Several new families of ribo- and arabino-nucleoside analogs will be synthesized by replacing the pentose ring with amidrazones, amidoximes and guanidines, leading to unprecedented chemical entities. These entities contain two uncommon structural elements (C=N, arylhydrazino linkage), neither of which is found in database searches of synthetic nucleosides evaluated at NIH for biological activity. However, they are clearly recognized by nucleoside processing enzymes like nucleoside hydrolase, and will be screened against nucleoside kinases, DNA polymerases, and reverse transcriptases. (4) Efforts to synthesize carbocyclic glycosidase inhibitors, like the trehalase inhibitor trehazolin, will focus on a stereoselective new route to pseudopentoses and pseudo-aminopentoses, and on glycoprotein and glycolipid analogs of these novel glycomimetics.