Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule

A new era has begun in the chemotherapeutic treatment of AIDS with the marketing of the first generation of peptidomimetic HIV protease inhibitors from Roche, Merck and Abbott. Owing to the potential drug resistance problems associated with HIV mutations, a main emphasis in the search for the next generation of HIVPR drugs is in the area of structurally different cyclic nonpeptides. This article reviews the different approaches that have been undertaken to find or design cyclic nonpeptides that are capable of displacing the structural water molecule usually associated with the peptidomimetic class of inhibitors. The favorable entropic effect from water displacement and preorganization can lead to smaller and more potent inhibitors with improved therapeutic potential.