Synergistic Inhibition of Human Immunodeficiency Virus Type 1 in vitro by 6-0-butanoylcastanospermine (MDL 28574) in Combination with Inhibitors of the Virus-Encoded Reverse Transcriptase and Proteinase

The anti-human immunodeficiency virus type 1 (HIV-1) activity of the α-glucosidase 1 inhibitor 6-0-butanoylcastanospermine (MDL 28574) was assessed in combination with the 2′,3′-dideoxynucleoside analogues zidovudine (AZT), didanosine (ddl) and zalcitabine (ddC). MDL 28574 was also evaluated in combination with the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine and the HIV proteinase inhibitor saquinavir (Ro-31-8959). Drug interactions were examined by the isobologram technique and by calculating combination indices (C.l.s). In all cases synergistic inhibition of HIV-1 replication was observed. In three-drug combinations, a marked synergistic antiviral effect was also observed, with C.I. values in the range 0.35-0.44 for MDL 28574 in combination with AZT and nevirapine, and in the range 0.34-0.67 for MDL 28574 in combination with AZT and saquinavir. Moreover, the combination of MDL 28574 with other drugs did not produce detrimental effects on cell division. MDL 28574 is currently in clinical trials and may have an important role in combination chemotherapy for HIV infections.