ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease
- 1 December 1998
- journal article
- clinical trial
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 42 (12), 3218-3224
- https://doi.org/10.1128/aac.42.12.3218
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 ( K i = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC 50 ], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC 50 , ≤0.06 μM). 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 EC 50 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 EC 50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.Keywords
This publication has 22 references indexed in Scilit:
- Human Serum Attenuates the Activity of Protease Inhibitors toward Wild-Type and Mutant Human Immunodeficiency VirusVirology, 1998
- A Controlled Trial of Two Nucleoside Analogues plus Indinavir in Persons with Human Immunodeficiency Virus Infection and CD4 Cell Counts of 200 per Cubic Millimeter or LessNew England Journal of Medicine, 1997
- A 24-week open-label Phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir)AIDS, 1996
- A Novel, Picomolar Inhibitor of Human Immunodeficiency Virus Type 1 ProteaseJournal of Medicinal Chemistry, 1996
- Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostereStructure, 1995
- Therapy for Human Immunodeficiency Virus InfectionNew England Journal of Medicine, 1993
- Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 proteaseAntimicrobial Agents and Chemotherapy, 1991
- Novel binding mode of highly potent HIV-proteinase inhibitors incorporating the (R)-hydroxyethylamine isostereJournal of Medicinal Chemistry, 1991
- Novel Fluorogenic Substrates for Assaying Retroviral Proteases by Resonance Energy TransferScience, 1990
- Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compoundsJournal of Virological Methods, 1988