Treatment Issues, Vol. 9, No. 2 - February, 1995
Vincent Pieribone, Ph.D.

What is Integrase?

HIV integrase is the virus's third enzyme (the other two are reverse transcriptase and protease). HIV uses integrase to incorporate its genes into a host cell's DNA. (The DNA form of the viral genes is produced by reverse transcriptase.) Inhibition of HIV integrase is an attractive therapeutic strategy since it would potentially protect healthy cells from infection thereby helping to bolster the immune system.

Promising Reports

At the conference, several laboratories presented ongoing work that may lead to agents that could block integrase's action. Notably, workers at the National Institute of Diabetes and Digestive and Kidney Diseases have determined the three dimensional structure of the central catalytic region of the enzyme. By knowing the structure of the enzyme's active site, scientists can begin to "design" compounds that bind to and possibly inhibit the enzyme. This "rational" approach proved successful in producing inhibitors of HIV protease.

Sometimes merely knowing the structure of the enzyme reveals a similarity of other related enzymes for which cross- specific inhibitors may already exist. Researchers have found that integrase resembles the structure of cellular RNAase H and another DNA binding protein termed mu-transposase.

Dr. Stephen Goff of Columbia University has used a novel molecular biologic technique to identify a host protein that binds to integrase and dramatically enhances its activity. Working with HIV integrase, the protein seems to help the viral genes to join properly with cellular DNA.

In screening the National Cancer Institute's drug library, Dr. Yves Pommier's laboratory has discovered three classes of compounds that are effective at blocking HIV integrase. These include DNA binding molecules, polyhydroxylated aromatic compounds and various nucleotides. Polyhydroxylated aromatic compounds naturally occur in a variety of plants. One active form is found in nectar from flowers and is used by bees to improve their hives. Some synthetic derivatives are ten times more potent at blocking integrase and have exhibited some anti-HIV activity in an NCI in vitro screening test.

Another promising lead reported at the meeting was a short inhibitory peptide that was extracted from a synthetic "combinatorial peptide library." These libraries consist of millions of different peptides with known sequences. By systematically testing mixtures with progressively fewer numbers of different peptides, one can identify the exact sequence of a peptide (or peptides) that has inhibitory activity.

Using a collection of compounds synthesized by Houghten Pharmaceuticals in San Diego, Dr. Ronald Plasterk's group from the Netherlands Cancer Institute found several lead peptides that inhibit HIV integrase. While these peptides are too large to be clinically relevant, they do provide structural constraints that chemists can use to create second generation molecules with more therapeutic potential.

Finally, the French company Rhône-Poulenc Rorer has been screening their large chemical collection and have identified several lead compounds. Probably the most exciting outcome of the conference was the fact that so many large pharmaceutical companies attended the meeting. This indicates a growing interest on their part in developing compounds active against integrase.

Potential Drawbacks

Integrase as a therapeutic target does have several possible pitfalls. While HIV reverse transcriptase and protease are required to act for a significant period of time during the viral life-cycle, integrase acts for only one brief step during infection of the cell. This reduces the chances that a drug will interfere with integration. Conversely, however, the intracellular levels of integrase may be extremely small, and this scarcity works in favor of an integrase inhibitor. Also, interfering with the integration step would not affect the yield of viable virus from infected cells. Since HIV seems to produce a great deal of mutations throughout its genes, inhibition of existing HIV integrase may merely cause the rise of drug-resistant mutant versions.

The hope is that a combination of therapies targeting different enzymes, including integrase, will convey lasting benefit to the infected person by reducing HIV's replication rate, and therefore the emergence of mutant strains.

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