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A Natural Edge: Nature Still Offers The Greatest Drug Diversity

Tom Reynolds

Today's drug developers use powerful, computer-driven techniques to churn out new molecular structures by the millions. But many scientists in the field say nature still offers the best foundation blocks for building truly novel, biologically active agents.

Some pharmaceutical companies have eliminated or cut back their natural products programs. Instead, they are betting on combinatorial chemistry, a method that emerged in the past decade and uses mathematical algorithms to generate countless variations on a single template molecule. The rapid assays used by drug makers demand a steady diet of new compounds to run through the screening mill. And combinatorial chemistry is the quickest way to make them.

Work on natural products, by contrast, moves at a more plodding pace, entailing the collection and preparation of specimens and the isolation, purification, and structural determination of active agents.

"When you've got a high-throughput screen that you've got to feed 50,000 things a week to, it has the inadvertent effect of making natural products research look slow, and expensive," said Jon Clardy, Ph.D., a chemist at Cornell University in Ithaca, N.Y. And there is the added problem — dramatized in the early 1990s by the dilemmas surrounding paclitaxel (Taxol®) — of finding a reproducible source.Go



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Yew forests are the source of paclitaxel.

 
Despite the defection of some drug makers, experts said natural products research will likely remain indispensable as a source of key leads to new anticancer agents and other drugs.

Unique Molecules

"Nature still produces the unique, novel molecules which are highly unlikely to be produced by synthesis, even with the combinatorial approach," said Gordon Cragg, Ph.D., chief of the National Cancer Institute's Natural Products Branch. "I don't think chemists at the bench would ever come up with a Taxol, for instance, from scratch."



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Dr. Gordon Cragg

 
Chris Ireland, Ph.D., a chemist at the University of Utah in Salt Lake City, noted that combinational chemistry samples a limited amount of three-dimensional space, and "a huge number of compounds does not necessarily mean a huge degree of diversity.

"When scientists tested the diversity of their combinatorial libraries," he said, "I think they got a real suprise when they found out they really are quite limited. The real strength of natural products is the diversity of structural types." Ireland is principal investigator of an NCI-sponsored cooperative group focused on natural products drug discovery.

Clardy predicted combinatorial chemistry "will play a major role in drug discovery," but much of that role, he said, will hinge on what is learned from natural products. Studying the chemicals made by living organisms has taught researchers about the properties that make molecules adept at getting into cells and binding proteins. One of the most important is a rigid, well-defined three-dimensional structure with a variety of functional groups that present attractive targets for receptors.

Another is stereochemical specificity, favoring either the left- or the right-handed stereoisomer of a molecule. Typically only one stereoisomer is active in binding to a receptor. While synthetic molecules usually occur in pairs of opposites, resulting in a 50/50 mix, nature makes specific isomers to meet the specific requirements of binding to proteins, which are made of the L (left) stereoisomer of amino acids.

One advantage of natural chemicals shows up in looking at pharmacokinetics — how drugs get into cells and bind to receptors, and the many ways they can fail. Unlike molecules cooked up in a lab, Clardy said, natural products " have already solved that problem" by virtue of the function they perform for the organism that makes them.

The "Right Stuff"

In fact, each approach has its strengths, which might be deployed most effectively when used together. Natural products can save time and money in the early phases of drug development by providing templates that have shown the "Right Stuff," at least in some biological system. These can then be modified by combinatorial chemistry in a search for the most active, least toxic variant.

The complexity and diversity of natural products makes them a "logical starting point," Ireland said. "Then the combinatorial chemists can modify it in every way they can imagine. . . . I think the clever people are recognizing that."

NCI's Cragg agreed. "I really think the methods can complement one another," he said. As an example, he pointed to the work of Stuart Schreiber, Ph.D., and colleagues at the Institute for Chemistry and Cell Biology at Harvard University in Boston (see News, Dec. 2, 1998).

The Harvard group synthesizes natural product-like molecules that they use as a starting point for combinatorial work. In the Aug. 26, 1998, issue of the Journal of the American Chemical Society, Schreiber and colleagues report the stereoselective synthesis of more than two million variants of one compound.

And in the March 30, 1999, Proceedings of the National Academy of Sciences, Schreiber and colleagues report the synthesis of an anti-tumor agent, phthalascidin, that is very similar to — but more easily synthesized and more stable than — the marine natural product ecteinascidin 743, and showed in vitro antiproliferative activity 10 to 1000 times greater than that of paclitaxel, adriamycin, and other drugs.

The ancient practice of seeking drugs in nature prefigures the new technologies in a profound way, Clardy observed, in that natural products are themselves the result of a sort of combinatorial process.

Throughout evolution, "gene modules are used over and over again to make variations on a theme," he said. Myriad modifications have produced an astounding diversity of organisms, and long-conserved genes can — with minor changes — produce wings in a chick and arms in a human. "Combinatorial chemistry is the same kind of chemistry, without the DNA," he said.

While rainforest plants and sea creatures capture the headlines, the humble microorganisms dwelling in soil have yielded more drugs than any other group of organisms. (Streptomycin was one of the first to be isolated. And this year, Merck and Co. Inc., Whitehouse Station, N.J., reported the isolation of a fungal metabolite that mimics the activity of insulin and is expected to improve diabetes treatment.) But recently research has stalled due to the difficulty of studying soil microbes in the laboratory. The species that can be easily cultured have been thoroughly scrutinized for valuable chemicals, and in fact are continually "rediscovered" via screening. But scientists estimate that these account for only 0.1% of the species, so the soil remains overwhelmingly terra incognita.

Untapped Wealth

"And most impressively," Clardy and colleagues at the University of Wisconsin, Madison, write in the October 1998 Chemistry & Biology, "the other 99.9% of soil microflora is emerging as a world of stunning, novel genetic diversity." They estimate that a gram of soil contains 1,000 to 10,000 new species.

To mine this untapped wealth, the group has developed a method to take genes from the culture-shy bugs and insert them into E. coli, which thrives in the petri dish. In this way, they plan to clone and analyze what they call the meta-genome of the soil, the collective genomes of all the microbes they can find.



             
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