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Protease Inhibitors as Treatments for AIDS

The AIDS virus produces an enzyme, HIV-1 protease, that carves up a large polypeptide precursor into several proteins essential for viral replication. Because of its importance to the virus, HIV-1 protease has been a target for drugs designed to inhibit it.

HIV-1 protease is an aspartyl protease, like pepsin and rhizopuspepsin discussed on the page before. This means that peptide analogs that mimic the substrate will inhibit HIV-1 protease in a similar manner.

The Chime structure at right shows HIV-1 protease bound to one such inhibitor, hydroxyethylene isostere. The inhibitor and the catalytic Asp groups are shown as wireframe models. This molecule mimics the transition state of the usual reaction in two ways:

The carbon that mimics the carbonyl carbon where the peptide bond is severed has a tetrahedral geometry, like the carbonyl carbon's transition state in the normal substrate.

This tetrahedral carbon has a bound hydroxyl group, which mimics the bound water molecule in the uninhibited enzyme.

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Because of the high rate of mutation of the AIDS virus, the use of single drugs like hydroxyethylene isostere is usually only effective for short time, since a strain of AIDS resistant to that drug develops quickly. The use of a combination of drugs such as protease inhibitors can overwhelm the ability of the AIDS virus to adapt. This is the origin of the "AIDS cocktail" that is currently helping AIDS patients lead nearly normal lives.