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NIH names Pitt to develop chemical 'library'

Friday, October 11, 2002

By Byron Spice, Post-Gazette Science Editor

Chemists at the University of Pittsburgh have been charged by the National Institutes of Health to develop new techniques for creating large chemical "libraries," a critical first step in attempts to develop new pharmaceuticals.

The National Institute of General Medical Sciences yesterday named Pitt and Boston University as Centers of Excellence in Chemical Methodologies and Library Development, awarding each $5.5 million for the first year of what will be a five-year program. Each center ultimately will receive about $10 million.

The Pitt team, headed by Peter Wipf, will be creating a chemical library of 50,000 "peptide mimetics," bits of protein that have been modified to enhance their medicinal properties. By synthesizing thousands of similar, but distinct compounds and then analyzing and categorizing their properties, researchers should be able to pick out ones that meet certain needs, such as for killing a particular tumor type.

But given the vast numbers of organic compounds that are theoretically possible and potentially of therapeutic use -- think of the number 1 followed by 60 zeroes -- 50,000 "is not even a drop in the bucket," said John M. Schwab, a chemist at the national institute who spearheaded the new program.

What the institute is really looking for is improved techniques for building these libraries.

Ten or 15 years ago, Schwab explained, medicinal chemists would synthesize and analyze new molecules one at a time, an expensive and time-consuming method. Now, the pharmaceutical industry relies on so-called combinatorial chemistry, which uses automation to create thousands of new molecules in one fell swoop.

One problem, however, is that all the techniques rely on starting with a core molecule, to which additional clumps of atoms are then attached in varying combinations. But only a relatively small number of these molecular "scaffolds" work very well, Schwab said. Likewise, the types of reactions known to work reliably in combinatorial methods is limited.

As a result, chemists realize that though their experiments can churn out thousands of chemical compounds at a time, these new libraries often have much in common with previous libraries, Schwab said.

So, in addition to creating new libraries, the Pitt and Boston centers will be trying to develop new scaffolds and new methods of facilitating chemical reactions. Though combinatorial chemistry is less common in academia than it is in industry, both the Pitt and Boston faculties already have a proven capability for doing combinatorial chemistry, Schwab said.

In addition to heading the new center of excellence at Pitt, Wipf is director of Pitt's Center for Combinatorial Chemistry. Kay Brummond will be vice director of the library project, which will include chemists Dennis Curran, Scott Nelson and Stephen Weber. John Lazo, chairman of pharmacology at the Pitt medical school, and Billy W. Day, director of the Proteomics Core in the Schools of the Health Sciences, also will participate.


Byron Spice can be reached at bspice@post-gazette.com or 412-263-1578.

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