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Imitating evolution with gene engineering leads to new drug candidates

STANFORD -- Chemical engineers at Stanford University have successfully applied an unusual genetic engineering approach for creating drug candidates to a new class of molecules typified by the powerful antibiotic erythromycin.

This approach, which the scientists first reported last year, is called an evolutionary simulator because it mimics the effect of natural selection on the enzymes that cells use to produce biologically active molecules. It was initially developed using the enzymes that produce natural compounds called aromatic polyketides. Found in most organisms, polyketides have been the source of a number of valuable antibiotic, anti- cancer and immunosuppressant drugs.

Writing in the July 21 issue of the journal Science, the researchers - Assistant Professor Chaitan S. Khosla, graduate student Camilla Kao and Leonard Katz from Abbott Laboratories - report that they have now applied this technique to a more complex set of enzymes that produce a second type of polyketide, called modular polyketides. One of the first genetically engineered molecules produced in this fashion was a close analogue of erythromycin.

When drug companies begin looking for a new drug and have no place to start, they first screen 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, so another way to identify lead molecules could be very useful, Khosla said.

The alternative method the researchers are developing reproduces the evolution of biological pathways that make natural compounds. Thus far, their work has focused on the polyketide family. To imitate the evolutionary process, the researchers genetically engineered a simplified system that approximates their idea of what the first polyketide- producing organism must have been like. After showing that the altered bacterial cells were capable of producing polyketides, 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.

Last December, they reported the production of the first five aromatic polyketides using this approach. Since then, they have developed a number of related strategies that more than quadrupled the repertoire of the genetically engineered compounds produced.

"A large number of these do not have natural analogues, so we appear to be opening a door to interesting molecules that have not been found in nature," Khosla said.

The scientists' goal is to develop the genetic, enzymatic and chemical strategies required to produce large numbers of novel polyketides. They figure that 1,000 or more compounds would create a commercially valuable chemical library. Last year, Stanford University applied for a patent on the process and has licensed the rights to Exogene Corp., a California biotechnology company for which Khosla has served as a consultant.

The production of polyketides is actually a by-product of the group's basic research, which is understanding how 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 a new version of these enzymes, they learn more about how they function.



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