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COMBINATORIAL REARRANGEMENTS Potential binding molecules in dynamic library self-assemble to give best fit Rebecca Rawls In a major step toward producing what he calls "the synthetic chemist's equivalent of catalytic antibodies," chemistry professor Jeremy K. M. Sanders and his colleagues at the University of Cambridge have developed a dynamic solution in which potential binding molecules assemble themselves into the best combination to bind to a particular target molecule. The work "is a very nice example of a new area known as dynamic combinatorial chemistry," explains Andrew D. Hamilton, chemistry professor at Yale University. "It shows how one can use an equilibrating mixture of molecules to generate a dynamic library, in this case a dynamic collection of potential binding molecules. It's one of the first examples to show that one can identify a single component from such a complex equilibrating mixture that binds reasonably strongly to a target." The immune system's ability to use a repertoire of preformed building blocks to rapidly construct new antibodies that bind tightly to target molecules is the inspiration for the dynamic combinatorial approach, Sanders says. "We're trying to invent a system whereby the optimum receptor can be assembled automatically around whatever you want to recognize." The current experiment is an important step toward that goal, he says. "It's the first time anybody has actually isolated a new receptor using the approach." Adapted from Angewandte Chemie PICK A WINNER Modified peptides that form a dynamic combinatorial mixture of cyclic oligomers, at left, zero in on the one cyclic trimer that best binds to acetylcholine when that biomolecule is added to the reaction. Concentration of the trimer increases more than 50-fold when acetylcholine is present. Cambridge chemistry graduate student Graham R. L. Cousins, postdoctoral fellow Ricardo L. E. Furlan, and their colleagues modified proline molecules to allow them to join together into cyclic molecules by means of covalent hydrazone linkages [Angew. Chem. Int. Ed., 40, 423 (2001)]. Under mildly acidic conditions, the hydrazone bonds continually break and re-form, so that the cyclic molecules are constantly changing their size and composition, producing a dynamic mixture of molecules ranging from dimers to assemblagesof more than a dozen linked peptides. The thermodynamically favored ring is the dimer, Sanders notes, and the chemists have shown that when the system is given a few hours to reach equilibrium, dimers become the most abundant component present. But that changes when acetylcholine is added to the solution. Only cyclic trimers can bind strongly to acetylcholine, and when they do, they become more stable and less likely to break down. "You amplify the molecule you want by stabilizing it," Sanders states. "Every molecule that is made that's not useful as a receptor just gets destroyed again, and the only ones that remain in the solution are the ones that bind to acetylcholine." SANDERS "Chemists interested in designing and synthesizing supramolecular catalysts have to be greatly encouraged by this latest finding to come out of the Sanders group," says chemistry professor J. Fraser Stoddart of the University of California, Los Angeles. "In this dynamic combinatorial library, the system responds to the demands of the templating 'key' to produce its matching 'lock.' Potentially, it turns chemists with keys into locksmiths who can assemble the right locks at the drop of a hat." The system demonstrates an approach that, if perfected, could be widely useful. "The idea," Sanders explains, "is that if you want to make a receptor, for example, for a drug molecule, you simply have a dynamic combinatorial mixture, put in your drug molecule, and you will assemble around the drug molecule the optimum receptor for it." The experiment is beautiful and gives an impressive result, notes Steven C. Zimmerman, chemistry professor at the University of Illinois, Urbana-Champaign. He remains to be convinced, however, of the long-term potential of the dynamic combinatorial approach. It's an approach, Zimmerman says, that's most likely to be useful for "very, very large and diverse libraries, those not accessible by parallel synthesis, where it is difficult or impossible to isolate any single member without some type of amplification." And for such large libraries, "there are questions about whether one can significantly shift the population of library members, given the enormous potential for competitive binding." |
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