ANTIVIRAL PROPERTIES OF AMINODIOL INHIBITORS AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS AND PROTEASE

A series of aminodiol inhibitors of human immunodeficiency virus type 1 (HIV-1) protease were identified by using an in vitro peptide cleava ge assay. EMS 182,193, EMS 186,318, and EMS 187,071 protected cells ag ainst HIV-1, HIV-2, and simian immunodeficiency virus infections, with 50% effective doses ranging from 0.05 to 0.33 mu M, while having no i nhibitory effect on cells infected with unrelated viruses. These compo unds were also effective in inhibiting p24 production in peripheral bl ood mononuclear cells infected with HIV-1 IIIB and against the zidovud ine-resistant HIV-1 strain A018C. Time-of-addition studies indicated t hat EMS 182,193 could be added as late as 27 h after infection and sti ll retain its antiviral activity. To directly show that the activity o f these compounds in culture was due to inhibition of proteolytic clea vage, the levels of HIV-1 gag processing in chronically infected cells were monitored by Western blot (immunoblot) analysis. All compounds b locked the processing of p55 in a dose-dependent manner, with 50% effe ctive doses of 0.4 to 2.4 mu M. To examine the reversibility of EMS 18 6,318, chronically infected CEM-SS cells were treated with drug and vi rions purified from the culture medium. Incubation of HIV-1 particles in drug-free medium indicated that inhibition of p55 proteolysis was s lowly reversible. The potent inhibition of HIV-1 during both acute and chronic infections indicates thai these aminodiol compounds are effec tive anti-HIV-1 compounds.