The N-linked glycans of the HIV envelope proteins are important for receptor binding, virus uptake, and syncytia formation. Alteration of oligosaccharide addition, composition or processing leads to attenuation in HIV infectivity and cytopathicity due to aberrant folding, oligomerization, cleavage or transport of virion glycoprotein. SC-48334, n-butyl-deoxynojirimycin (BuDNJ), is an iminosugar which inhibits the endoplasmic reticulum alpha-glucosidase I resulting in biochemical modification of N-linked oligosaccharides. Inhibition of intestinal disaccharidases in vivo, however, can lead to carbohydrate malabsorption and diarrhea. Prodrug SC-49483 was developed to eliminate the GI side effects associated with oral administration of SC-48334. SC-49483 does not inhibit intestinal sucrase and is not antiviral in vitro but is converted to the active antiviral parent SC-48334 during absorption in the GI tract. In vitro studies show that SC-48334 inhibits syncytia formation approximately 5 uM) and reduces the yield of infectious virus in HIV infected cultures. Chronically infected cells treated with BuDNJ do not fuse with uninfected lymphoid cells and virions released from the treated cells are noninfectious. SC-48334 is a potent (EC50 = 43 uM), non-toxic (TD50 > 5 mM) inhibitor of HIV replication and cytopathicity in human peripheral blood mononuclear cells, including monocytes/macrophages, infected with primary clinical isolates and AZT resistant strains of HIV. SC-48334, in combination with AZT or DDI, is synergistic; in combination with inhibitors of the late stages in virus replication (e.g., protease inhibitors) it is at least additive. Virion-associated glycoprotein from treated cells is incompletely processed and carbohydrate analysis definitively shows immature glucosylation and provides evidence that glucosidase inhibition represents the biochemical basis for an antiviral activity of SC-48334. Analysis of the effect of SC-48334 on human bone marrow progenitor cells (CFU-GM and BFU-E studies) and pharmacological evaluation of uptake, intracellular steady-state concentration, and elimination T1/2 are in progress.

*alpha-Glucosidases/ANTAGONISTS & INHIB *Antiviral Agents/PHARMACOLOGY *HIV/PHYSIOLOGY *Virus Replication/DRUG EFFECTS *1-Deoxynojirimycin/ANALOGS & DERIVATIVES

www.aegis.org