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When the ancient Greeks were trying to conquer Troy, their main challenge was to get soldiers into the heavily fortified city. The solution, as everybody knows, was a giant wooden horse. Cell biologists today are facing a similar problem: they want to get foreign molecules—such as toxic drugs—into cancer cells. One way to do this is to design compounds mimicking natural ligands that a cell normally takes up without suspicion; however, once inside, these compounds reveal their toxic potential. Blake Peterson, a chemist at The Pennsylvania State University, decided to break with this tried-and-tested method and chose another path to penetrate a cell. In a recent article in the Journal of the American Chemical Society, he lays out an alternative strategy to give cells the capability of taking up foreign cargo (Boonyarattanakalin S. et al., 2004).

“We became interested in the idea of trying to mimic receptors found on the cell surface using synthetic molecules,” explains Peterson. His group set out to engineer receptors that insert into the cell membrane and, after delivering their cargo to intracellular vesicles, recycle back to the plasma membrane for the next round of transport (Fig. 1). It was this last aspect that posed the greatest challenge to the Peterson team, until they found that an amine derivative of cholesterol rapidly cycled between the cell surface and intracellular vesicles. Having settled on cholesterylamine for a membrane anchor, the researchers constructed a functional receptor by adding a linker and a cargo-binding domain. Surprisingly, Peterson found that it was the structure and length of this linker that determined the efficiency of the recycling mechanism. In general, the longer the linker, the better the receptors recycled. Even though this observation is intriguing and could shed light on basic trafficking mechanisms, the main application of these synthetic receptors is the transport of molecules into cells. This synthetic chemistry approach for accessing the cellular interior offers great versatility. Chemists may be able to engineer artificial receptors with different binding motifs that facilitate the uptake of virtually anything, to the benefit or destruction of cells. For example, in drug delivery, tumor cells carrying a specific synthetic receptor might be made more susceptible to toxic drugs.

Figure 1
figure 1

Synthetic receptors cycling from the plasma membrane to intracellular vesicles and back to the plasma membrane.

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Although such applications hold promise, there are still big hurdles to overcome. One is to show that these synthetic receptors, which have primarily been tested on cells in culture, also work in animals. Peterson is cautiously optimistic; his team has preliminary results from a vertebrate model in which the receptors are incorporated into cellular membranes. Whether they still work as receptors and how toxic they are in an animal over a longer time span is now being tested.

Nonetheless, this approach offers an innovative solution to an old problem. If Odysseus had met Blake Peterson, maybe the Greeks would have dismissed the idea of a horse and instead presented the Trojans with a city gate containing a clandestine portal.