Green Light For Chemokine Receptors

April 09, 1997

Potent inhibition of HIV-1 entry into macrophages has been demonstrated for the first time. A Glaxo Wellcome collaborative study showed that a chemically modified chemokine, AOP-RANTES, inhibited HIV-1 entry not only into lymphocytes but also into macrophages. This inhibition was achieved at the nanomolar level.

"We are excited by these results, which encourage us to believe that chemokine receptors are going to be suitable targets for drug discovery", said Dr Amanda Proudfoot, a research scientist at Glaxo Wellcome's Geneva Biomedical Research Institute. "There is still a long way to go and questions remain about the eventual clinical utility of chemokine receptor antagonists - but these results are very promising."

This research is the latest stage in the process of validating chemokine receptors as drug targets and further research is underway to explore their potential in the treatment of HIV/AIDS and asthma. Glaxo Wellcome has already set up a screening programme to hunt for small molecule antagonists of the chemokine receptor CCR5.

Chemokines, or chemoattractant cytokines, are a large family of small proteins that regulate the movement of white blood cells. They exert their effects by binding to specific receptors. Researchers believe that chemokine receptor antagonists hold considerable potential for the treatment of diseases such as asthma, arthritis and HIV/AIDS.

Chemokines in asthma

Certain chemokines, including one called RANTES, are potent activators and promote migration of T cells, eosinophils, and monocytes - cells that play an important role in inflammation. In particular, eosinophils are thought to contribute to tissue damage in the airways of patients with asthma.

Recent research from Glaxo Wellcome has shown that a modified form of RANTES, Met-RANTES, can effectively block this activity. The researchers hope that a drug with similar properties will eventually lead to a new class of anti-inflammatory drugs especially useful for patients whose asthma is not well controlled by current therapies.

Chemokines in HIV/AIDS

Two chemokine receptors, CCR5 and CXCR4, have been found to act as co-receptors essential for HIV infection. The CD4 receptor plus one of these chemokine receptors is required for HIV entry into host cells. HIV uses the CCR5 receptor to gain entry into macrophages and lymphocytes during initial infection and the asymptomatic phase of disease. Later on, because HIV mutates rapidly, viruses able to infect T cells using the CXCR4 receptor become more prominent. Symptoms appear after this later form of HIV predominates.

Significant progress has been made towards validating CCR5 as a drug target. Three chemokines, RANTES, MIP-1a and MIP-1b, interact with the CCR5 receptor and have been shown to inhibit the entry of HIV into lymphocytes. A recent Glaxo Wellcome collaborative study with the Chester Beatty Institute in London published in Science (Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist, Science, 11 April 1997, 276: 276-279 shows that in contrast to the naturally occurring chemokine, a chemically modified version of RANTES, AOP-RANTES made by Dr Robin Offord of the University of Geneva, is significantly more potent, and in addition is also able to block HIV entry into macrophages.

As Dr Proudfoot explained, "HIV resides in certain tissues, in cells such as macrophages, during the early phase of disease, when blood levels of virus are still undetectable. Our findings suggest a treatment approach that could be used before AIDS symptoms appear to stop HIV from spreading to cells in the tissues."

AOP-RANTES blocks HIV entry by fully occupying all CCR5 receptors on the macrophage surface. Scientists hope that by attacking HIV early on, they can delay or stop progression to disease. All existing HIV/AIDS treatments attack viral enzymes; chemokine receptor antagonists would offer a completely new approach - targeting host cells to prevent HIV entry. Dr Tim Wells, the Glaxo Wellcome chemokine project leader in Geneva, said "We believe that our findings suggest an alternative treatment approach that could be used alongside current therapies and have set up a screening programme to look for candidate molecules."

Chemokine receptor antagonists as medicines

There is undoubtedly great interest in chemokine receptor antagonists as potential medicines. CCR5 and CXCR4 are 7 transmembrane, G protein linked receptors, a type of receptor well known to pharmaceutical companies like Glaxo Wellcome, many of whose existing drugs also block 7 transmembrane receptors.

However, chemokines are vitally important immune system components and interfering with their normal function could have side effects. Data are already available that suggest that blocking CCR5 may not lead to serious side effects; people with mutations in the CCR5 receptor do not have any obvious health problems. Further, the mutations in the CCR5 receptor appear to confer some resistance to HIV infection. There are several cases of people with mutant CCR5 receptors who have repeatedly had high risk contact with HIV infected patients, but have themselves remained HIV negative.

For further information contact:

Philip Connolly, Group Public Affairs, Glaxo Wellcome plc: Tel: +44 181 966 8185, Fax: +44 181 966 8827

Dr Amanda Proudfoot, Glaxo Wellcome Research & Development S.A., Geneva Biomedical Research Institute: Tel +41 22 706 9800

Emma Weitkamp, Hayhurst Conington Cripps Ltd: Tel: + 44 1483 414182, Fax: +44 1483 414157

GlaxoSmithKline US

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