Protease inhibitors are a new class of drugs that works by blocking the HIV protease. Once the protease is blocked, HIV makes copies of itself that cannot infect other cells. These protease inhibitors seem to be less toxic and seem to have less severe side affects than other anti-AIDS drugs (nucleoside analogs like AZT) Saquinavir , ritonavir, and indinavir are the three main HIV protease inhibitors available today. For a comparison chart of the three protease inhibitors click here.

History

Scientists had been tryng to design and synthesize inhibitors of human resin (protease in the kidneys). Human renin plays a key role in regulating blood pressure. It was believed that a renin inhibitor could be a highly effective drug for controlling hypertension. The HIV protease is similar in structure and function. Therefore, there was already an abundance of knowledge and experience in building inhibitors to proteases of this type. All the protease inhibitors were modeled after the compounds first developed for renin.

How do protease inhibitors work?

Protease inhibitors resemble the protein chain that the protease cuts. The protease inhibitor binds to the site that normally binds the protein chain. Once the inhibitor binds the protease cannot bind the protein to be cleaved and is not functional. In order to make optimum use of the genes, HIV makes long nonfunctional polypeptide chains that are precursers to the actual proteins and enzymes. Although new viruses are made, if the polypeptide chain is uncleaved, the virus cannot make the necessary enzymes to infect other cells. Protease inhibitors do not cure AIDS, they can only decrease the number of infectious copies of HIV.

This picture shows the HIV protease (purple and green) complexed with the inhibitor (spacefill). This prevents the substrate from reacting with the protease and thus, the polypeptides are not cleaved. For veiwing of the complex in rasmol click on the picture. oooooooooo oooooo ooo oo ooo ooo ooooooooo ooo ooo oooooo ooo oo oooooo oo oooooooo oooooo ooooo oo oooooooooo oooooooo ooooooo ooooooo ooooo ooooo oo ooooo oooo. ooooo ooooo ooooo oo oo ooooooo.

This shows the interaction between HIV protease inhibitor and the residues that hydrogen bond to the inhibitor. Aspartate A25 and B25 and isoleucine A50 and B50 are hydrogen bonded to the inhibitor. ooooo ooooo oooo oooooooooooo ooooooooooooooooooo ooo o o oooooooo oo ooooo oooooooo oooo oooo oooo ooo ooo oooo ooo.

Saquinavir

Saquinavir which has the trade name Invirase was the first protease inhibitor to be approved by the FDA (December 1995) for the treatment of HIV infection. One problem with the drug was that it had limited oral bioavailability (did not absorb into the body well). Saquinavir must be taken with meals that have a high fat content. However, the high fat diet does not overcome the inhibitor going through extensive metabolism in the liver by the hepatatic cytochrome P450 3A system. There have been studies done to increase the absorption of squinavir into the body. Some studies have found that taking the drug with grapefruit juice increases the absorption. There were also many clinical trials done using cominations of saquinavir/AZT, saquinavir/AZT/ddC, and AZT/ddC. After 48 weeks of treatment, people taking the saquinavir/AZT comination had an average increase of 74 T-cell. People taking AZT and ddC had an increase of 72 T-cells and with saquinavir/AZT/ddC there was an increase of 111 T-cells. Clearly showing that combination drug therapy is more promising than single drug therapy.

Ritonavir

Indinavir

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Table of Contents

HIV Protease

HIV Protease Inhibitors

Saquinavir

Conclusion

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