Approaches to the design of effective HIV-1 protease inhibitors

Recently, western countries have recorded a decrease in the death rate impu ted to AIDS. This success has been largely attributed to the presence on th e market of chemotherapies that inhibit the infectivity of the predominant causative agent, the HIV-1 virus, by targeting essential viral enzymes. One of these is the protease (HIV-1 PR) whose activity is a prerequisite for v iral replication. Two main sires have been identified as potential targets for the inhibition of HIV-1 PR, the active site and the interface, the latt er being largely responsible for the stabilization of the enzyme dimeric st ructure. The compounds that have reached clinical application so far target the active site of HIV-1 PR. These molecules act as transition state analo gues and result from modifications of the peptidic scaffold into peptidomim etics. In order to improve their bioavailability, systematic biological scr eening and de novo design have been used to suggest new non-peptide inhibit ors combining both antiviral potency and favorable pharmacokinetic properti es. In parallel, compounds targeting other potential sites of inhibition ha ve been tested. Peptides and peptidomimetics based on the terminal sequence of the enzyme, a site which is proposed to be less susceptible to mutation s, have been shown to lead to HIV-1 PR inactivation. Cupric ion was describ ed to bind a sequence on the protease surface, which includes cysteine and histidine residues, leading to the inhibition of the enzyme. In the future, these non-active site inhibitors could provide an alternative in anti-HIV drug combination strategies.