HIV-1 protease: mechanism and drug discovery.

It has now been two decades since acquired immunodeficiency syndrome (AIDS) was first reported by the US Center for Diseases Control (CDC). A few years later, it was found that a retrovirus called human immunodeficiency virus (HIV) is the causative agent in AIDS. In a short time, AIDS increased to epidemic proportions throughout the world, affecting more than 40 million people today and killing so far more than 22 million (UNAIDS, 2001). Since the outbreak of the AIDS epidemic, tremendous efforts have been directed towards development of antiretroviral therapies that target HIV type 1 in particular (HIV-1). The identification of the HIV retrovirus and the accumulated knowledge about the role of the different elements in its life cycle led researchers around the world to develop inhibitors that target different steps in the life cycle of the virus. One of these targets is HIV-1 protease (HIV PR), an essential enzyme needed in the proper assembly and maturation of infectious virions. Understanding the chemical mechanism of this enzyme has been a basic requirement in the development of efficient inhibitors. In this review, we summarize studies conducted in the last two decades on the mechanism of HIV PR and the impact of their conclusions on the drug discovery processes.