Structure-based design of symmetric inhibitors of HIV-1 protease.
HIV-1, the causative agent of AIDS, encodes a protease that processes the viral polyproteins into the structural proteins and replicative enzymes found in mature virions. Protease activity has been shown to be essential for the proper assembly and maturation of fully infectious HIV-1. Thus, the HIV-1 protease (HIV PR) has become an important target for the design of antiviral agents for AIDS. Analysis of the three-dimensional structures of related aspartic proteinases, and later of Rous sarcoma virus protease, indicated that the active site and extended substrate binding cleft exhibits two-fold (C2) symmetry at the atomic level. We therefore set out to test whether compounds that contained a C2 axis of symmetry, and that were structurally complementary to the active site region, could be potent and selective inhibitors of HIV PR. Two novel classes of C2 or pseudo-C2 symmetric inhibitors were designed, synthesized and shown to display potent inhibitory activity towards HIV PR, and one of these, A-77003, recently entered clinical trials. The structure of the complex with A-74704 was solved using X-ray crystallographic methods and revealed a highly symmetric mode of binding, confirming our initial design principles. These studies demonstrate that relatively simple symmetry considerations can give rise to novel compound designs, allowing access to imaginative new templates for synthesis that can be translated into experimental therapeutic agents.
Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland.
J
J
Erickson
D
D
Kempf
D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000737:chemistry*; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry
D017320:HIV Protease Inhibitors; D013402:Sugar Alcohols; C065300:A 74704; D016333:HIV Protease; D014633:Valine