Case Study 1: Peptidomimetic HIV Protease Inhibitors

There are nine peptidomimetic drugs on the market for the treatment of acquired immunodeficiency syndrome (AIDS), and at least four in clinical development for treatment of hepatitis C virus (HCV) infections. The array of drugs against AIDS, which is caused by human immunodeficiency virus (HIV) infection, includes peptidomimetic compounds that target the virally encoded aspartic protease enzyme. HIV-1 is a virus belonging to the family of Retroviridae, and possesses a diploid RNA genome HIV-1. The general mechanism of peptide bond hydrolysis catalysed by aspartic proteases takes advantage of a water molecule between the two carboxylates of catalytic aspartates. Information on the structure, function and catalytic mechanism of the HIV-1 protease has enabled the design of specific inhibitors towards this enzyme. The application of these inhibitors in combination with drugs targeting other viral targets is central to antiretroviral therapy.