| RESEARCH |
Associate professor of biochemistry Romas J. Kazlauskas and coworkers at the University of Minnesota, St. Paul, and associate professor of chemistry James L. Gleason and coworkers at McGill University, Montreal, are collaborating to develop "pseudodynamic" combinatorial techniques. These address a key drawback of DCC technology: fundamental limitations on the degree of selectivity or amplification that can be achieved, owing to the thermodynamics of the equilibrium processes used in DCC. In pseudodynamic combinatorial chemistry, an irreversible destruction reaction is used to destroy poor binders kinetically by removing them from solution. When compounds bind strongly to a target, they're sequestered from the destruction reaction. They thus get "selected" and concentrated as poorer binders are depleted. Last year, Kazlauskas, Gleason, and coworkers showed that an irreversible protease-catalyzed hydrolysis reaction could be used to select and concentrate aryl sulfonamide dipeptides that bound with high affinity to a carbonic anhydrase target [J. Am. Chem. Soc., 124, 5692 (2002)]. More recently, they found that when this hydrolysis process is linked with several cycles of dipeptide synthesis, the best binding dipeptide is concentrated in greater than 100-fold excess over more weakly binding dipeptides. This selectivity is more than an order of magnitude greater than would have been achieved in a conventional DCC study, the researchers say. |
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