Glycoprotein processing is a complex, poorly understood means by which the sugar groups of a previously glycosylated protein are "trimmed" or "processed" in a particular sequence to obtain a specific pattern of glycosylation. The specificity is important to a number of recognition processes and is the basis for cell-cell and cell-virus interactions. The trimming is accomplished by a set of highly specific enzymes which recognize particular sequences of sugars. One such enzyme, Glucosidase I, is responsible for cleaving the three terminal glucose residue in the oligosaccharide structure (Glc.sub.3 Man.sub.9 GlcNAc.sub.2). Clearly, inhibitors of such an enzyme could be useful in treating diseases and conditions in which glycoproteins are involved.
Certain viruses including the retroviruses have, in addition to the usual vital capsid, an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed, the lipid of the vital membrane is probably derived directly from the membrane of a previously infected host cell; however, the glycoprotein of the viral membrane is unique to the virus itself and is coded for by the viral genome. Infection of a host cell by a glycoprotein coated virus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus. Subsequently, the virus and cell membranes fuse and the virion contents are released into the host cell cytoplasm. Thus the glycoprotein envelope of the coated viruses plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes.
Interference with the formation of the viral envelope glycoprotein could prevent the initial virus-host cell interaction or subsequent fusion or could prevent viral duplication by preventing the construction of the proper glycoprotein required for the completion of the viral membrane. Inhibitors of Glucosidase I may be valuable agents in the treatment of membrane-coated viral disease and metastatic tumors. S. P. Sunkara et al., Biochem and Biophys Research Commun. 148(1), 206 (1987); A. Karpas et al., Proc. Natl. Acad. Sci. USA, 85, 9229 (1977); B. D. Walker et al., Proc. Natl. Acad. Sci. USA, 84, 8120 (1987).
Tumor metastasis is also a process which relies on the cell surface glycoproteins of a traveling tumor cell to bind to the cell surface of a distant tissue. The binding and subsequent cell fusion relies extensively on the cell surface glycoprotein and clearly interfering with the proper development of cell surface glycoproteins would prevent or reduce tumor metastasis. Glucosidase I inhibitors are known to be useful in preventing tumor metastasis and thus applicants' novel compounds are potential antimetastatic agents.
USPTO Backgrounds
USPTO Backgrounds