Turning antibodies into chemists.

Turning antibodies into chemists

To create exquisitely specific tools for future chemical missions ranging from destroying viruses to building new proteins, scientists have been teaching antibodies to act like enzymes.

Antibodies recognize and bind to particular chemical structures -- usually molecular intruders in the body -- with a specificity unmatched in the world's molecular menagerie. By luring chemical starting materials, or reactants, and then helping them overcome initial energy barriers, enzymes rapidly trigger thousands of biologically crucial chemical transformations.

Since 1986 scientists have been reporting ways of conferring the reaction-speeding skills of enzymes to antibodies, which also specifically bind reactant molecules while ignoring all others. Most efforts so far have involved making stable molecular analogs that chemically resemble a reaction's so-called "transition state," a fleeting molecular structure chemists believe must form before reactants can change into products. By injecting these analogs into mice, scientists can use the animals' immune systems as factories for making catalytic antibodies with binding pockets that custom-fit the actual transition state of the reactant molecules. Once bound in this way, reactants quickly rearrange into products.

Peter G. SChultz of the University of California, Berkeley, reports new tactics for fitting the antibodies' binding sites with additional chemical features that could enable scientists to make many more catalytic antibodies tailored for almost any chemical transformation. In one versatile tactic, Schultz and his colleagues attached a flexible molecular "handle" near the binding site of antibodies. "Now we have an antibody that has a handle on it with which we can presumably introduce any reactive group we want," he says.

Moreover, says Schultz, "we can put reporter molecules on there to make antibodies into sensors." In one example, the researchers attahced a fluorescent molecule to the handle. When the particular chemical that the antibody binds docks into the binding site, the fluorescence dims. By monitoring for such changes, the group can infer whether the chemical is present in a sample.

Several scientists report making catalytic antibodies that break the tough amide bond between amino acids, which string together into enzymes and other proteins. Without enzymatic help, seven years would pass before the average amide bond in a protein broke, remarks molecular biologist Richard A. Lerner of the Research Institute of Scripps Clinic in La Jolla, Calif. "Acting as specific chemical scissors, these antibodies may have the ability to cut up a virus or break apart a blood clot," says Kim D. Janda of Scripps. He reports making antibodies that can cut about three specific amide bonds in an hour. Although improvement must precede their application, such antibodies could enable scientists to cut and paste strings of amino acids into virtually any sequence to make new proteins, says Lerner.