Merck unveils integrase inhibitor

Keith Alcorn
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This article is more than 22 years old.

Merck scientists unveiled the fruits of the company’s efforts to develop an inhibitor of integrase, the newest target in the HIV life cycle, at the XIV International AIDS Conference in Barcelona yesterday.

The agent is called L-870,810, and acts at the second stage of the integration process. Integrase is essential for the integration of HIV DNA into the human cell nucleus. Integration happens in two stages – assembly of viral DNA in preparation for integration, and viral strand transfer – and previous integrase inhibitor investigations have focused on the first stage, with disappointing results.

L-870,810 was developed from a class of compounds called diketones, which were tweaked by chemists to reduce a tendency for very high protein binding that might have rendered the drugs impossible to absorb except in great volumes.

Glossary

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

protein

A substance which forms the structure of most cells and enzymes.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

phase I

The first stage of human testing of a new drug or intervention, typically involving a small number (10-100) of participants who do not have the condition the drug is intended to treat. Phase I clinical trials evaluate safety, side-effects, dosage and how a drug is metabolised and excreted in the body.

life cycle

In HIV, refers to the series of steps that the virus follows to multiply in the body. The process begins when HIV encounters a CD4 cell. The seven steps in the HIV life cycle are: 1) binding; 2) fusion; 3) reverse transcription; 4) integration; 5) replication; 6) assembly; and 7) budding.

The resulting agent appears highly potent against HIV-1, with an IC95 of 102 nM, compared to an IC95 of approximately 12,000 nM for the Shionogi/Glaxo SmithKline integrase inhibitor unveiled at the Ninth Retroviruses conference earlier this year in Seattle. Merck scientist Steve Young told aidsmap that these comparisons were carried out in 50% human serum in order to capture the effect of protein binding.

The compound is also active against multi-drug resistant virus exposed to all currently available classes of antiretrovirals, and seems much less prone to resistance than other classes. Integrase mutations selected using a predecessor compound resulted in a 11-fold increase in IC50 (to 88 nM), although other mutations were associated with much smaller losses in sensitivity. Pharmacokinetic studies in rats and dogs indicate a much higher exposure (AUC). Since the drug is not metabolised by the cytochrome p450 system, no significant interactions with other antiretrovirals are anticipated. However, this lack of interaction means that the agent will probably be dosed twice daily, with no potential for pharmacokinetic boosting.

Antiviral activity has been confirmed by assessing the accumulation of 2LTR circles – unintegrated circles of proviral DNA – a marker for integrase deficient viral replication.

Phase I studies in healthy volunteers have begun, and if the drug proves to be safe and effective, Phase III studies could be underway within two years, confirming Robert Gallo’s prediction earlier in the conference that we will be hearing a lot more of integrase by the time of the next International AIDS Conference in 2004, in Bangkok.

References

Young SD et al. L-870,810: discovery of a potent HIV integrase inhibitor with potential clinical utility. XIV International AIDS Conference, Barcelona, abstract LbPEA9007, 2002.

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