New HIV drugs edge towards approval


New HIV Drugs
Two promising new drugs for treating HIV, the virus that causes AIDS, could receive regulatory approval in the US later this year. The development of the new drugs is significant because each works in a different way from the existing arsenal of anti-HIV products. This could help to overcome the problem of patients developing resistance. The drugs are maraviroc, developed by Pfizer, and raltegravir, from Merck and Co.  

Maraviroc works by blocking the activity of a receptor called CCR5, present on cells that are the target of HIV. CCR5 has been the focus of intensive investigation since it was discovered some years ago that a mutation in the gene encoding the receptor results in immunity to HIV infection, suggesting that the receptor is crucial to the infection process. In Phase III trials - the latter stage of testing new therapies - the virus dropped to undetectable levels in more than 40 per cent of patients receiving maraviroc for 24 weeks, double the rate in those patients who received placebo.  

In trials of raltegravir, a compound that inhibits integrase, a crucial enzyme in HIV's infection cycle, virus levels became undetectable in 60 per cent of patients, compared with 35 per cent in the control group. Both drugs are administered orally. 

While there are around 20 anti-HIV drugs currently in use, these fall into only four classes. The most effective treatment is achieved when drugs of at least two classes are used in combination, as patients can develop resistance to a whole class of drug after long-term use.  

Maraviroc was discovered by researchers at Pfizer in the UK following the identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Its mechanism of action was established using cell-based assays, where it blocked the binding of a viral envelope glycoprotein gp120 to CCR5, preventing the virus from entering the cell. 

New HIV Drugs
Raltegravir, on the other hand, inhibits integrase, the enzyme that stitches HIV DNA into the host cell's DNA to hijack the cell's machinery and force it to replicate the virus. Integrase is an attractive target for therapy because there is no similar enzyme in human cells. High-throughput screening identified a number of  beta-diketo acids as inhibitors of the enzyme, which work by binding to the enzyme's active site. The Merck compound is a naphthyridine derivative of one of the  beta-diketo acids identified in this way. 

Ben Cheng, deputy director of the Forum for Collaborative HIV Research in Washington, DC, told Chemistry World, 'The new developments are potentially beneficial for many patients, particularly those who have been on therapy for some years and who have developed resistance to the drugs that are currently available. The appearance of these two new drugs together is significant because the longer we only have the existing classes of drug, there is an increased likelihood that people will develop resistance. If these drugs are approved, there is the opportunity to combine both classes, hopefully increasing the likelihood of successful treatment.'  

Simon Hadlington

 

Gang of four

There are currently some 20 approved drugs for treating HIV, falling into four classes.  

Gang of four

T cell infected with HIV virus

© NIBSC / SCIENCE PHOTO LIBRARY

Protease inhibitors work by interfering with the HIV protease enzyme, preventing the assembly of proteins during the latter stages of viral replication. There are various drugs that inhibit reverse transcriptase, the enzyme needed to transcribe the viral RNA into DNA; these  reverse transcriptase inhibitors are incorporated into the growing DNA strand, whereupon subsequent synthesis is halted because the rogue molecules do not contain the necessary chemical groups to allow the next link in the DNA chain to be forged. The first such drug was Retrovir, which contains AZT.  Non-nucleoside reverse transcriptase inhibitors also attack reverse transcriptase, but attach to a different part of the enzyme to stop it translating viral RNA into DNA. There is only a single drug in the fourth class,  fusion inhibitors . Infection of a CD4 cell of the immune system by HIV requires the virus to fuse to the host cell, a process mediated by a glycoprotein. The drug, Fuzeon, which must be injected by the patient, is a biomimetic peptide that interferes with the glycoprotein binding step.