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Bacteria are organisms that are equipped to reproduce themselves; antibiotics attack that machinery. But a virus is a parasite: It invades a host cell and co-opts the cell’s own machinery to make copies of itself—thousands of copies at once, which means thousands of chances to mutate and develop drug resistance. A drug that disables a part of the human cell that helps the virus reproduce, though, could stop it with little risk of resistance. “And if you can identify a host function that HIV, fl u, and Ebola all require, you can have one drug that is active against all three—a broad-spectrum antiviral,” says Michael Kurilla of the National In sti tute of Allergy and Infectious Diseases (NIAID).

The key is finding the right target—a gene, and the protein it encodes, that the human cell doesn’t need but the virus does. Human DNA contains more than 20,000 genes, but in any given cell at any given time, many are dormant; some, for instance, are only switched on during embryonic development. With the human genome now fully decoded, investigators can search for targets systematically by disabling individual genes in many cells and seeing what happens. Zirus, a company in Buford, Georgia, uses a three-step process (see opening illustration); it begins by infecting cells with a harmless retrovirus, which splices itself randomly into human DNA, knocking out any gene it interrupts. Other groups are disabling selected genes with matching bits of RNA. If the cell survives without a particular gene and is now resistant to infection, that gene-protein combo is a promising target for a drug.

The first such drug, Pfizer’s Maraviroc, is already being used to treat HIV infections; it blocks a cell-surface protein that acts as a receptor for the virus. San Diego–based NexBio has recently begun clinical trials of a compound called Fludase that inactivates the receptors through which both swine flu and seasonal flu enter respiratory cells. NIAID is vigorously supporting such research. “Over the next 20 to 30 years there will be a paradigm shift in the way we approach infectious diseases,” Kurilla says. “I think this will be emblematic of 21st-century medicine.” —Josie Glausiusz

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