No abstract

The potency of therapeutic regimens containing human immunodeficiency virus (HIV) protease inhibitors is related to the ability to maintain concentrations of drug in the plasma of patients that are sufficient for blocking viral replication. The estimation of concentrations required for in vivo activity using in vitro assays is complicated by the fact that extensive binding of many protease inhibitors to serum proteins attenuates their antiviral potency. To provide insight into the relative in vivo potency of current protease inhibitors, we assayed their in vitro activity against wild-type and mutant HIV in the presence of human serum (HS). Using this assay, ABT-378, a new protease inhibitor with trough levels in humans far in excess of the EC50 in the presence of 50% HS, was identified. The antiviral activity of ABT-378 was only modestly attenuated by HS, in contrast to ritonavir, saquinavir, and nelfinavir. Examination of the effect of individual serum components suggested that the activity of ABT-378 is affected predominantly by binding to alpha1-acid glycoprotein (AGP) while the activity of ritonavir is modulated by both AGP and albumin. The method described here may provide insight into the in vivo potency of protease inhibitors and be useful for the preclinical evaluation and selection of new protease inhibitors for clinical studies.

No 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.