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Making More Drugs...continued

Millions of potential drugs, all of them (nearly) useless

Combinatorial chemistry essentially means reacting a set of starting chemicals in all possible combinations. For chemists used to pure, discrete compounds it sounded messy, and initially most of them stayed away. But gradually researchers came up with ways to deal with the complicated mixtures and unmanageable numbers, and chemists forgot their misgivings.

It started with peptides. Everyone knows that peptides -- short stretches of the protein molecules that do all the work in the cell -- are lousy drugs. They get eaten up in the stomach and the survivors rarely get into cells. And yet somehow Mario Geysen’s strategy for making peptides has become the accepted way of making drugs in the 1990s.

Working at Melbourne University in Australia, Geysen thought he could make lots of peptides in almost the same amount of time that someone else could make one. Each peptide was made on the end of a ‘pin,’ and for each step in the reaction the pin was dipped into a dish with a new chemical. The trick was to line up hundreds of pins in an array, such that they aligned with hundreds of tiny dishes. Procedures like washing and drying could now be done on all the reactions at once. For some steps -- adding an amino acid as a new link to the peptide chain, for example -- a different chemical had to be added to each dish. But time was still saved, as the chemical reactions could run in parallel. The result was termed a library of peptides.

The next year, in 1985, Richard Houghten of the Scripps Research Institute (La Jolla, Calif.) came up with a similar scheme, but this time each peptide was made attached to bits of plastic enclosed in a mesh bag, dubbed a tea bag. Houghten went on to form the combinatorial chemistry company Houghten Pharmaceuticals, which is now called Trega Biosciences, Inc. (San Diego, Calif.).

The third and most enduring format came in 1991, when Kit Lam of the Arizona Cancer Center (Tucson, Ariz.) made a library of over one million different peptides. "That really showed not only to the peptide chemist but to the medicinal chemist that this could be useful," says Lam.

Plastic beads for
combinatorial chemistry.
Each peptide was on a different plastic bead. The beads -- each with a diameter close to that of a human hair -- made possible a crucial mixing step. The original Geysen method, an example of the parallel approach, requires a separate pin and reaction dish for every final product. But Lam’s split/pool method saves by doing reactions as mixtures, and it is now the most common method in combinatorial chemistry.

In the first set of reactions the first link is added to the peptide chain: either A, B, or C. The beads from these three separate reactions are mixed, washed, and re-divided. Each new sample now contains a mixture of A, B and C beads. One sample is reacted with D, another with E, and another with F. The mixing ensures that all possible combinations (AD, AE, AF, BD.....) come out at the end. We end up with nine (3x3) final products after six (3+3) reactions.

"You can instantly see that a parallel method will give you pure compounds," says Czarnik. "But [with split/pool] I can make 10,000 compounds in a four-step reaction sequence with just ten reaction vessels."

That’s 10x10x10x10 compounds with forty (10+10+10+10) reactions. You get down to a total of ten beakers only if you are prepared to wash up in between each of the four steps.


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