Enzyme Inhibition in the Treatment of AIDS

Enzyme Inhibition in the Treatment of AIDS

A key strategy in the treatment of acquired immunodeÞciency syndrome (AIDS) has been to develop speciÞc inhibitors that selectively block the actions of enzymes unique to the human immunodeÞciency virus (HIV), which causes AIDS. Many laboratories are working on this approach to the development of therapeutic agents. Three key enzymes are current targets for AIDS therapyÑreverse transcriptase, integrase, and protease.

One of the most important target enzymes is HIV protease, an enzyme essential to the production of new virus particles in infected cells. HIV protease is unique to this virus. It catalyzes the processing of viral proteins in an infected cell. Without these proteins, viable virus particles cannot be released to cause further infection. The structure of HIV protease, including its active site, was known from the results of X-ray crystallography. With this structure in mind, scientists have designed and synthesized compounds to bind to the active site. Improvements were made in the drug design by obtaining structures of a series of inhibitors bound to the active site of HIV protease. These structures were also elucidated by X-ray crystallography. This process eventually led to several compounds marketed by different pharmaceutical companies. These HIV protease inhibitors include saquinavir from Hoffman-LaRoche, ritonavir from Abbott Laboratories, indinavir from Merck, Viracept from Pfizer, and amprenavir from Vertex Pharmaceuticals. (These companies maintain highly infor-mative home pages on the World Wide Web.)

The most recent target is the viral enzyme called integrase, which is needed for the virus to copy itself in the host cell. A recent drug made by Merck, called MK-0518, inhibits the inte-grase enzyme. Treatment of AIDS is most effective when a combi-nation of drug therapies is used, and HIV protease, integrase, and reverse transcriptase inhibitors play an important role. The use of multiple inhibitors for the key viral enzymes allows levels of each to remain below toxic levels to the cell.