Targeting HIV protease: from peptidomimetics to non-peptide inhibitors

The identification of HIV-1 protease as a target for therapeutic intervention against AIDS, soon followed by the resolution of its three-dimensional structure, has had a major impact on drug-design methodologies. The possible HIV-1 protease inhibitors that have been synthesized number in the thousands and exhibit amazing chemical diversity, but only a few happen to be useful for human therapy. This review covers the development of some of these inhibitors, the reasons for this limited success, current therapeutic problems and challenges remaining ahead.