Making More Drugs...continued
Now for the useful stuff
Geysen, Houghten and Lam had started with peptides because Bruce Merrifield of Rockefeller University, New York, had already worked out how to make peptides anchored to a solid material like a plastic bead. Before Merrifields work, which earned him the 1984 Nobel prize in chemistry, there was a painstaking purification of the growing peptide chain after each amino acid was added. Now the chemists could add huge amounts of chemicals, driving reactions to completion in a short time. Excess chemicals can then be washed away, leaving only the beads and therefore the attached peptide product. Others were quick to take advantage of this system to make short stretches of DNA called oligonucleotides.
But oligonucleotides and peptides are equally lousy as drugs, and for similar reasons. What was needed was a way to make similarly huge numbers of chemicals, but chemicals that looked like drugs.
The company researchers who tackled this -- at Chiron Corporation, Emeryville, Calif., and Affymax Research Institute, Santa Clara, Calif. -- initially stayed with the links-in-a-chain approach. Chirons peptoids, made in 1992, looked like peptides but the linkages were altered to make them more stable.
The next evolutionary step came the following year. "People realized that one could think more broadly and make unnatural structures; that one didnt have to make polymeric structures at all," says Mark Gallop, director of combinatorial chemistry at Affymax. "You could make chemicals like the organic heterocycles that pharmaceutical companies had historically turned into drugs." Jonathan Ellman and colleagues at the University of California, Berkeley, and Sheila DeWitt and the bioorganic group at Parke Davis made the first libraries of these circular chemicals -- molecules in the same family as the sedative valium.
They were not alone. "They just happened to be the first ones to publish, but there were lots of people doing similar things at the same time," says Lam. "The field just exploded around that time."
A circular chemical is a perfect starting point for a library. Hundreds of different side-branches can be added to the various chemical groups poking out of the circle. This is now true combinatorial chemistry, where one of a large number of possible building blocks is added to each of several variable sites on a molecule.