ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease

Abstract

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

FIG. 1

Modeled overlay of ABT-378 (blue) and ritonavir (brown) in the active site of HIV protease (green). The conformations of HIV protease and ritonavir are derived from the X-ray crystal structure of the HIV protease-ritonavir complex (21a). The conformation of ABT-378 was modeled as described in the Materials and Methods section. A partial surface of the protein is shown in green to highlight the active-site pockets. A surface is shown on ABT-378 (blue dots) to illustrate how the inhibitor efficiently fills the active site. A surface is shown for ritonavir (brown dots) over the P3 isopropylthiazolyl group, which interacts with the side chain of Val 82 (labeled).

FIG. 2

Mean ± standard error of the mean plasma ABT-378 levels after oral dosing with 10 mg/kg singly and in combination with various doses of ritonavir in rats. Open circles, dosed singly; closed circles, codosed with 1 mg of ritonavir per kg; open squares, codosed with 5 mg of ritonavir per kg; closed squares, codosed with 10 mg of ritonavir per kg.

FIG. 3

Inhibition of the metabolism of ABT-378 and saquinavir by ritonavir in rat and human liver microsomes. Values represent the means of triplicate determinations. Dashed lines, rat microsomes; solid lines, human microsomes; filled circles, ABT-378; open circles, saquinavir.

FIG. 4

Mean ± SD plasma ABT-378 levels in healthy human volunteers following administration of a single 400-mg dose. Dashed line, ABT-378 dosed singly; solid line, ABT-378 dosed with 50 mg of ritonavir; dotted line, EC₅₀ of ABT-378 against wild type (WT) HIV in vitro.