The Pharmaceutical Journal
Vol 270 No 7253 p821
14 June 2003

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New England Journal of Medicine abstract (more)

Block to viral entry is target for HIV treatments in development

With current interest in a drug that blocks the fusion of the HIV virus with target cells, American doctors have reviewed other agents in development that interfere with the entry of HIV-1 into cells (New England Journal of Medicine 2003;348:2228).

They report that the binding of glycoprotein 120 (gp120), present on the HIV cell membrane, with the T-cell's CD4 receptor has been identified as a target. An early "decoy" receptor had shown limited activity, but a monoclonal antibody against CD4 (TNX-355) has shown blocking activity after a single dose. PRO542 contains CD4 receptor domains and also acts as a decoy, with evidence of activity in early trials. BMS-806 binds gp120 to block interaction with CD4 but in vitro studies have shown variable activity.

Dextran sulfate is a polyanionic compound that seems to interfere with attachment in a non-specific way. The reviewers add that, although the compound displayed excessive toxicity in the clinic, it demonstrated that the gp120-CD4 interaction could be blocked by charge-induced interference. PRO2000 and cyanovirin N are other attachment inhibitors on trial as topical microbicides.

Several agents bind the chemokine receptors on target cells, known as CCR5 and CXCR4. The compound SCH-C competitively binds to CCR5 and is in phase I/II development. A monoclonal antibody against CCR5 is in a preclinical stage and an inhibitor of CXCR4 has shown minimal activity in patients after intravenous administration.

Agents like enfuvirtide, which attach to the gp41 protein on the HIV cell surface, can prevent the virus fusing with the T-cell membrane and can thus prevent infection. T-1249 is another membrane fusion inhibitor in phase I/II development. Investigators are now working on a five-helix protein that inhibits the replication of HIV-1 by related mechanisms.