The protease inhibitors represent one of the best examples of the application of basic scientific knowledge to rational drug design. Relatively soon after the discovery of HIV, researchers were able to elucidate the genetic structure of the virus -- a process that identified an array of structural and regulatory gene products. Within the pol region of the virion's genetic structure (Figure 1, below), researchers found codons for HIV protease, reverse transcriptase, and integrase (Figure 1, central blue band), which are essential to the maturation of the virus.

Although the genetic sequence of the HIV protease enzyme was described soon after the discovery of the virus itself, the three-dimensional structure of the gene was not demonstrated until several years later, when the protease gene product was expressed an crystallized. Once the structure had finally been identified, however, researchers were able to begin designing compounds that specifically targeted the active site of the HIV protease.

Protease enzymes are proteins that cut other proteins at highly specific locations. The HIV protease is an aspartyl protease enzyme similar to mammalian proteases like renin. However, HIV protease activity is unique for HIV proteins, and in the host there is virtually no cross-reactivity between the HIV protease and normal human protease gene products. It is this lack of cross-reactivity that gives the protease inhibitors their outstanding safety profile.

The HIV protease enzyme cleaves polyproteins of the virus into essential functional protein products during the maturation process of the virion (Figure 1, green and red bars). This critical process occurs as each new virion buds forth from the membrane of an HIV-infected cell and continues after the immature virus is released from the cell. If the polyproteins are not cleaved, the virus fails to mature and is incapable of infecting a new cell.

As their name implies, the protease inhibitors are able to inhibit the function of the native protease enzyme. They exert his inhibitory effect by disabling the enzyme before it can cleave the gag/pol polyprotein into its essential products. Like a key perfectly fitted to a lock, the protease inhibitor simply locks up the enzyme, rendering it ineffectual (Figures 2 and 3).

It is this genetically engineered fit that accounts for the extraordinary effectiveness of the protease inhibitors, and it is the pinpoint accuracy with which they target HIV protease -- and only HIV protease -- that accounts for their extremely high tolerability.