Dual CCR5/CXCR4 Antagonist Blocks HIV Entry and Infection

[Guest guest]

Dec 28 - AIDS investigators are encouraged by early results with a novel anti-HIV agent that blocks replication of HIV via selective dual antagonism of two key HIV coreceptors -- CCR5 and CXCR4. The compound, AMD3451, is a low-molecular-weight N-pyridinylmethyl cyclam analog being developed by AnorMED of British Columbia.

It has shown consistent antiviral activity against a broad range of R5, R5/X4, and X4 strains of HIV-1 and HIV-2 in various T-cell lines, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. The decrease in the average 50% inhibitory concentration (IC50) with AMD3451 in these cell lines ranged from 1.2 to 26.5 microM.

AMD3451 also inhibits R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs, investigators report in the December issue of the Journal of Virology, with an IC50 of 1.8 to 7.3 microM.

"Because of its dual interaction with both CXCR4 and CCR5, and, consequently its potential to block cellular infection of X4, R5, and R5//X4 viruses, AMD3451 can be considered an important antiviral lead compound for the further development of an effective microbicide," they conclude.

In comments to Reuters Health, principal investigator Dr. Dominique Schols from the Rega Institute for Medical Research in Leuven, Belgium said: "I think what is important is that microbicidal compounds can be developed that target both chemokine receptors, which are both crucial for HIV entry and infection. This avoids the discussion of which coreceptor is the most important in viral infection."

"If potency can be increased, maybe one drug can inhibit all HIV variants as they all need CCR5 and/or CXCR4, so less escape routes are possible for the virus," Dr. Schols theorized.

J Virol 2004;78:12996-13006.

[Guest guest]

An AMD CXCR4 antagonist is scheduled to begin phase II study in patients in the ACTG.

Jules Levin

Dec 28 - AIDS investigators are encouraged by early results with a novel anti-HIV agent that blocks replication of HIV via selective dual antagonism of two key HIV coreceptors -- CCR5 and CXCR4.

The compound, AMD3451, is a low-molecular-weight N-pyridinylmethyl cyclam analog being developed by AnorMED of British Columbia.

It has shown consistent antiviral activity against a broad range of R5, R5/X4, and X4 strains of HIV-1 and HIV-2 in various T-cell lines, peripheral blood mononuclear cells (PBMCs), and monocytes/macrophages. The decrease in the average 50% inhibitory concentration (IC50) with AMD3451 in these cell lines ranged from 1.2 to 26.5 microM.

AMD3451 also inhibits R5, R5/X4, and X4 HIV-1 primary clinical isolates in PBMCs, investigators report in the December issue of the Journal of Virology, with an IC50 of 1.8 to 7.3 microM.

"Because of its dual interaction with both CXCR4 and CCR5, and, consequently its potential to block cellular infection of X4, R5, and R5//X4 viruses, AMD3451 can be considered an important antiviral lead compound for the further development of an effective microbicide," they conclude.

In comments to Reuters Health, principal investigator Dr. Dominique Schols from the Rega Institute for Medical Research in Leuven, Belgium said: "I think what is important is that microbicidal compounds can be developed that target both chemokine receptors, which are both crucial for HIV entry and infection. This avoids the discussion of which coreceptor is the most important in viral infection."

"If potency can be increased, maybe one drug can inhibit all HIV variants as they all need CCR5 and/or CXCR4, so less escape routes are possible for the virus," Dr. Schols theorized.

J Virol 2004;78:12996-13006.

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