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

The valine at position 82 (Val 82) in the active site of the human immunode ficiency virus (HIV) protease mutates in response to therapy with the prote ase inhibitor ritonavir. By using the X-ray crystal structure of the comple x of HIV protease and ritonavir, the potent protease inhibitor ABT-378, whi ch has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (K-i = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effe ctive concentration [EC50], 0.006 to 0.017 mu M), and maintained high poten cy against mutant HIV selected by ritonavir in vivo (EC50, less than or equ al to 0.06 mu M). The metabolism of ABT-378 mas strongly inhibited by riton avir in vitro. Consequently, following concomitant oral administration of A BT-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 und er the concentration curve of ABT-378 in plasma by 77-fold over that observ ed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exce eded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.