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Imitating Mother Nature to produce potential new drugs

STANFORD -- Chemical engineers at Stanford University have developed a technique that imitates the way nature makes an important class of the biologically active molecules found in many pharmaceuticals.

Details of the novel approach, which the scientists describe as genetically engineered biosynthesis using an evolutionary simulator, are being reported in the Dec. 3 issue of Science and in an upcoming issue of the Journal of the American Chemical Society.

"There is a large class of natural compounds, called polyketides, that are the source of a number of therapeutically active molecules," said Assistant Professor Chaitan Khosla, who heads the research group."We have developed a new way of making polyketides, including those with novel structures, using genetic engineering."

When drug companies begin looking for a totally new drug, they begin by screening thousands of natural products, looking for a "lead" molecule that exhibits some of the desired activity, even if it is very weak. Once they have such a molecule, synthetic chemists and pharmacologists can dramatically improve upon it by applying traditional organic chemistry. Ninety-nine percent of these new lead molecules come from previously uncharacterized or poorly characterized natural sources, Khosla said.

"Our premise has been that we may be able to provide what nature provides, and perhaps even more, and do so in a more convenient fashion," Khosla said.

Many of the useful compounds identified in natural sources over the years have turned out to be polyketides. For nearly 50 years, they have been used as powerful antibiotics. Tetracyclines and erythromycin are well known-examples. More recently, other members of this family have been found to possess significant anti-cancer and immunosuppressant properties.

To provide an alternate source of new polyketides, Khosla, working with Stanford graduate students Robert McDaniel and Camilla Kao, research associates Hong Fu and Susanne Ebert-Khosla, and Professor David A. Hopwood from the John Innes Institute in the United Kingdom, started with the natural enzymes, called polyketide synthases, that produce these molecules. They genetically engineered a simplified system that approximated their idea of what the first polyketide-producing organism must have been like.

After showing that the altered bacterial cells were capable of expressing a representative enzyme, which, in turn, produced a polyketide, the scientists began replacing strategic bits of DNA with genetic material from other polyketide-producing organisms and demonstrated that this alters the enzyme in ways that produce novel polyketides.

Because they believe that this process is comparable to the way in which chemical diversity evolved within this class of natural compounds, the group calls their system an evolutionary simulator. Earlier this year, Stanford University applied for a patent on the process and has licensed it rights to Exogene Corp., a California biotechnology company for which Khosla has served as a consultant.

In the published papers, the researchers describe the first five polyketides that were produced in their evolutionary simulator. Of these, two had previously been found in natural products and have structures very similar to polyketides with strong anti-cancer properties. One of the two is used as a commercial dye stuff. The other three polyketides had novel structures. Since then, the researchers have produced six additional polyketides, none of which had been seen before.

"Although the statistics of such small numbers can be misleading, the fact that only two out of 11 molecules were previously unknown raises the possibility that this approach may produce types of polyketides that current screening practices miss," Khosla said. Another possibility is that the process creates types of compounds that natural organisms do not synthesize for one reason or another, he said.

The scientists' ultimate goal is to produce large numbers of such compounds, but they are still far from that point. Successfully producing more than 10 compounds is enough to "wake people up," but they must produce a 1,000 or more compounds to create a chemical library that might have commercial value, according to Khosla. At this point, he expressed confidence that they will be able to reach the 100-molecule level. They are exploring directions that could increase this number to 1,000-10,000, but are not sure yet how successful these will be, he said.

Actually, the generation of novel polyketides is a fortunate byproduct of the group's basic research, which is understanding how the polyketide synthase enzymes work. These are extremely large, multifunctional molecules that can catalyze as many as 100 different chemical reactions at the same time. Each time the scientists make an enzyme, they learn more about how it works.

Such an incremental approach is necessary, Khosla said, because "the enzymes are so complicated that it would take a scientist an entire lifetime to completely understand just one of them.

"We are indeed fortunate that these enzymes can be manipulated to produce potentially useful molecules while providing us with fundamentally new insights into the basic rules of biosynthesis."



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