R. Dani Bolognesi still remembers the afternoon in 1994 when one of his research colleagues, Tom Matthews, ran into his office at Duke University with some exciting news. While searching for something that might work as a vaccine against HIV, Matthews had stumbled upon a compound that blocked the AIDS virus from binding to--and thus infecting--healthy cells. "I remember it as if it were yesterday," says Bolognesi, now CEO of the company he co-founded to explore the compound's commercial potential. "He said, 'You're not going to believe this. I've got something that's blocking fusion!'"
It turns out that the compound Matthews identified doesn't work as an AIDS vaccine, but it may still make a very good AIDS drug. It belongs to a family of molecules known as entry inhibitors that, as the name suggests, prevent HIV's entry into healthy immune cells. While none are yet available in pharmacies, they are probably the most promising new class of anti-HIV drugs under review. Bolognesi's company, Trimeris, based in Durham, N.C., collaborates with Hoffman-LaRoche and is already in the final stages of human testing with one compound and in the earliest phases of testing with a second. Other biotech firms, including Progenics Pharmaceuticals in Tarrytown, N.Y., are right behind it. Progenics currently has two compounds in human trials. Together, these drug candidates represent a sophisticated new generation of antiviral compound--drugs born of a better understanding of how HIV works, at the molecular level, inside the body.
Entry inhibitors, for example, include at least three families of potential drugs designed to block key steps in HIV's entry into a cell. Scientists know that in order for HIV to establish an infection, it first needs to make contact with the right cells. They also know that HIV binds very quickly to a particular section on the surface of a type of immune cell known as CD4. You can think of these points of entry as windows or doors into the cell; in order to get inside without destroying the cell (which has machinery the virus needs to reproduce itself), HIV has to find and pick the lock. To do this, it links simultaneously to an adjacent section on CD4 known as a cytokine receptor. Once the virus has bound to both CD4 and the cytokine, chemical changes take place that alter the structure of the cell's membrane, and the lock is "tripped." Fusion between the virus and the cell occurs, and HIV is free to spill its genome into the cell and begin replication.
Trimeris' compound, called T-20, blocks the final structural contortion from taking place. For this reason it and a second candidate, T-1249, are known as fusion inhibitors. Progenics has been testing a different type of entry inhibitor, a molecular decoy for CD4 whose job is to find, bind and lure HIV away from the real CD4 cells.