Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease

Abstract

Specific processing of the human immunodeficiency virus (HIV) gag and gag-pol polyprotein gene products by the HIV protease is essential for the production of mature, infections progeny virions. Inhibitors of HIV protease block this maturation and thus prohibit the spread of HIV in vitro. Previously, we reported a series of novel, symmetric inhibitors of HIV protease designed to match the C2 symmetric structure of the active site of the enzyme. In response to the poor aqueous solubility of those lead compounds, we designed a series of analogs with substantially improved (greater than 10(4) fold) solubility. These inhibitors showed anti-HIV activity in H9 and MT4 cells at 0.05 to 10 microM, and in most cases, they were noncytotoxic at concentrations in excess of 100 microM. Further examination of one inhibitor (A-77003) revealed broad-spectrum activity against both HIV types 1 and 2, including azidothymidine-resistant HIV, in a variety of transformed and primary human cell lines. After administration of the inhibitors to rats, short half-lives and, with two notable exceptions, moderate oral bioavailability were observed. Additional pharmacokinetic studies in dogs and monkeys revealed the potential utility of A-77003 as an intravenous anti-HIV agent.

Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy.

“…In contrast to the four antiherpesvirus drugs, the HIV protease inhibitor A77003 (a ritonavir analog) in a separate experiment (Fig. 2 B ) had no effect on KSHV production even at 1.5 M, a concentration 10-20-fold higher than its IC 50 in comparable HIV antigen release assays (26). To control for potential nonspecific cytotoxicity induced by the drugs, in each experiment we examined (at several time points) the viability of cells in treated and untreated cultures, using trypan blue exclusion.…”

Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug

“…During the initial selection for resistance to ABT-77003 (Kageyama et al, 1992;Kempf et al, 1991Kempf et al, , 1993Kort et al, 1993), viruses gradually and sequentially accumulated up to a total of four specific changes in the protease. These four changes were previously noted for viruses with reduced sensitivity to a number of different HIV-1 protease inhibitors (Condra et al, 1995;Kaplan et al, 1994;Otto et al, 1993;Patick et al, 1995).…”

“…Among them, a variety of inhibitors of the virus protease have been shown to possess remarkable antiviral activity and several are currently under evaluation in clinical trials involving HIV-infected patients (Debouck, 1992;Ho et al, 1995;Kageyama et al, 1992;Kempf et al, 1991;Kort et al, 1993;Lam et al, 1994;Roberts et al, 1990;Vacca et al, 1994). The infectivity of retrovirus particles requires the cleavage of precursor polyproteins into several structural and enzymatically active mature proteins (Hunter, 1994).…”

Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

“…Each inhibited step has its own dose-response curve, which can be described with IC 50 and m values. Thus,…”

“…At least 2 drug-specific parameters are necessary to fully describe these curves: the concentration of drug producing 50% inhibition (IC 50 ) and the slope (m), which describes the steepness of the curve. The fraction of infection events unaffected (f u ) by the drug at a concentration D is given by the median effect equations (24) Standard semi-log dose-response curves plot f u vs. log D. In comparing multiple drugs, it is useful to normalize the drug concentration by the IC 50 . Plots of this kind obscure the importance of the slope parameter ( Figure 1A).…”