Update on a proteinase inhibitor

HIV PROTEINASE INHIBITORS: The HIV proteinase enzyme has been identified as a potential target for antiretroviral therapy, as inhibition of this enzyme leads to the generation of immature, non-infectious virions. There are several proteinase inhibitors in development; the first to enter clinical trials was saquinavir. DEVELOPMENT OF SAQUINAVIR: Saquinavir, a transition-stage analogue of an HIV proteinase cleavage site, was developed using computer-led rational design techniques. It is a highly specific inhibitor of HIV-1 and -2 proteinases, with antiviral activity at concentrations 1000-fold less than those causing cytotoxicity. EUROPEAN CLINICAL EXPERIENCE WITH SAQUINAVIR: Three European clinical studies involving 202 patients have been conducted with saquinavir at doses of 25, 75, 200 and 600 mg three times a day. Two studies were dose-ranging monotherapy trials, one in asymptomatic or mildly symptomatic patients not previously treated with zidovudine, the other in patients with advanced HIV infection who had been treated with zidovudine. The third study was a combination therapy trial with zidovudine in previously untreated patients with advanced infection. Saquinavir was well tolerated either alone or in combination with zidovudine. In the monotherapy studies, CD4 cell counts and estimates of viral load showed the best results with the 600-mg dose. The combination of saquinavir and zidovudine resulted in higher and more sustained increases in CD4 cell counts than with either drug alone. The CD4 cell counts favoured saquinavir at 200 and 600 mg in combination with zidovudine, although plasma viraemia and the RNA polymerase chain reaction indicated that the 600-mg dose (in combination) produced better responses.