Drugmakers seeking to block the activity of a protein may have a new strategy at their disposal, according to a paper published in the June 11, 2008, issue of Nature. Traditionally, drugs that block protein activities do so by binding the protein's active site, which in turn prevents the natural substrate from binding at that site, which ultimately inhibits the protein's activity. But there may be another way to skin that particular cat. The new paradigm proposes to prevent substrate binding by attaching the drug directly to the substrate instead of to the protein. In theory, this also would prevent the substrate from binding the protein's active site with the same effect of inhibiting the protein's activity.

The notion of interfering with protein-substrate binding by tying up the substrate may have several advantages over the traditional approach. For one thing, many of the protein-blocking drugs are monoclonal antibodies, themselves large proteins that can be difficult to deliver. Substrate blocking, on the other hand, might be accomplished with smaller molecules. In addition, substrates are often found circulating in the bloodstream, which may facilitate drug delivery.