Resistance to protease inhibitors

Excerpt

HIV-1 produces most of its viral proteins as large precursor proteins (Figure 1), including the Gag and the GagPol precursor proteins. The Gag precursor encodes the structural proteins of the virus, whereas GagPol encodes the three viral enzymes protease, reverse transcriptase (RT) and integrase. HIV-1 protease is responsible for the cleavage of these two precursor proteins at a number of different cleavage sites in a defined order, which results in the formation of mature infectious virus particles [–3].

The HIV-1 protease enzyme is a homodimeric enzyme comprising two identical symmetrical subunits of 99 amino acids (Figure 2a). In the middle of the enzyme, there is a cavity that forms the substrate-binding cleft and the active site of the enzyme lies at the bottom of the cleft. The top of the cleft is covered by two mobile flaps, which allow the substrate to enter or leave the cleft.