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A New Twist on Old Phage

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With increasing pressure to develop safer drugs faster and more efficiently, the antibody community has responded with a suite of next-generation approaches. Mostly, these techniques — some of them involve nanoengineering while others rely on more tried-and-true molecular biology techniques — offer improved target affinity and antibody potency with potential for other advances, such as thermostability, increased selectivity, and improved pharmacokinetics.

Antibodies aren't just for immunoassays. In the clinic, they can be formed to bind specifically to cancer cell surface markers, for instance, to initiate the immune response, or to bind elsewhere within a pathway to disrupt its function in maintaining a disease state. Typically, though, antibodies are large, weighing in at 150 kDa, and they're difficult to make.

"The next generation will look very different," says Greg Weiss, a professor of chemistry at the University of California, Irvine. "They're going to have different shapes; they're going to have better performance in terms of their production; they'll be less expensive to make; and they might even have better binding properties." Weiss has been working on a method of pinpointing better HIV drug targets using phage display. He's using the approach to track the evolution of the virus — and therefore, its ability to mutate rapidly and confer drug resistance — through one particular protein expressed on the surface of HIV, Nef.

Phage display has been around since the mid-'80s and has proven to be a useful tool for expressing a large collection of proteins on the surface of a virus, after which a scientist runs protein-binding assays that can select for a specific binding target. Because the virus "basically shrugs and goes about its viral business," it's a great way to look at binding properties of proteins on a large scale all at once, Weiss says.

A few years ago, a postdoc in Weiss' lab had the idea to use phage display to look at the evolution of drug resistance. "Drug resistance is sort of like a library," Weiss says. "The virus makes lots and lots of changes to the protein that's targeted by the drug, and then there's a selection. And [her] thought was, if we can do this, then we'd understand how drug resistance works, and even better, maybe we'd have some insight into how to avoid the development of drug resistance."

Their work led them to Nef, an accessory binding protein that HIV uses to "tailor its living room: down-modulate the immune system, control some cell signaling processes, basically make the cell a cozy hangout where it can produce lots of copies for itself," Weiss says. They then created a bunch of different versions of Nef, all mutated forms that appear in clinical HIV infection, and called this set of proteins the Nef "allelome." They hope to use this in further phage display assays to select for small molecule inhibitors to Nef that are specific to mutated forms, with the idea of stopping AIDS progression in patients with resistant forms of the virus.

"I think there's a lot of opportunity for applying this in cases where you have natural selection that is attempting to thwart your treatment," Weiss says, adding that it's a good tool to counter antibiotic, antiviral, and even anti-cancer drug resistance. "Potentially we can anticipate what kinds of conditions they might encounter in the clinic, that they might encounter resistance; this can give us a way then of countering that resistance before it even takes place."

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