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August 25, 2003
Volume 81, Number 34
CENEAR 81 34 p. 8
ISSN 0009-2347


HIV DRUGS

NO DOCKING HERE
Small-molecule inhibitor prevents HIV entry into cells

CELIA HENRY

Most approved HIV drugs inhibit either reverse transcriptase or protease to prevent viral replication. But many researchers are focusing on developing other drugs that prevent the virus from entering a cell in the first place.

A multidisciplinary team at Bristol-Myers Squibb in Wallingford, Conn., led by molecular biologist Pin-Fang Lin and chemist Nicholas Meanwell, now report a new compound that prevents viral entry. BMS-378806 works by binding to the viral envelope glycoprotein gp120 so the virus can't dock with the CD4 cell receptor [Proc. Natl. Acad. Sci. USA, published online Aug. 20, http://www.pnas.org/cgi/doi/10.1073/pnas.1832214100].

BMS-378806 shows excellent potency against many HIV-1 laboratory and clinical isolates and no significant cell toxicity in 14 cell lines. The compound is orally bioavailable in tests with dogs, rats, and monkeys. It works against strains that are resistant to protease and reverse transcriptase inhibitors. Resistance to BMS-378806, however, develops fairly rapidly in cell culture.

"Because of the rapid emergence of resistance to currently available anti-HIV drugs, additional safe and effective inhibitors are desperately needed," says Eric O. Freed, chief of the virus-cell interaction section in the HIV Drug Resistance Program at the National Cancer Institute, Frederick, Md. "Whether BMS-378806 will turn out to be clinically useful will require more study, but this compound certainly does exhibit a variety of promising characteristics."

In an accompanying commentary, Robin A. Weiss and Áine McKnight of the department of immunology and molecular pathology at University College London write that, although "BMS-378806 should be regarded as a first-generation molecule," it is "a most promising start."


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INHIBITOR The small-molecule BMS-378806 binds to the viral cell surface glycoprotein gp120, blocking the protein's interaction with the CD4 receptor.
ADAPTED FROM PNAS



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