New Method for Engineering Marine Compounds Shows Promise for Drug Development

Margo Haygood

11/16/06 Portland, Ore.

OHSU Professor Margo G. Haygood, Ph.D., as a member of a team of researchers led by University of Utah medicinal chemist Eric W. Schmidt, Ph.D., has assisted in the development of a new approach using genetic pathways in cyanobacterial symbionts of marine ascidians to engineer the production of a new cyclic peptide. Their research has important implications for the generation of new pharmaceuticals for cancer and other diseases using the rich genetic resources found in marine bacteria.

Cyanobacteria, one of the largest and most important groups of bacteria on earth, are found in various forms in every conceivable habitat where light is present. For their study, published on November 5 in Nature Chemical Biology online, the researchers collected 46 marine ascidians--commonly known as sea squirts--from Palau and Papua New Guinea in the tropical Pacific. The ascidians contained a particular symbiotic species of cyanobacteria called Prochloron didemni, each strain of which produces slightly different patellamides--cyclic peptides of seven or eight amino acids--that accumulate in the tissues of sea squirts and may help them to defend against predators.

Many of these chemicals have anticancer properties, but harvesting them in quantities for large-scale testing and production is impractical. Instead, researchers have traditionally synthesized such natural compounds in the lab using labor-intensive, time-consuming techniques. More recently, investigators have begun to use genes to make small molecules within laboratory strains of bacteria. This method is quite difficult, however, given the complexity of most genetic pathways and the lack of understanding about the relationship between changes in genes and differences in resulting synthesized compounds.

In their study, the Utah-led researchers used the relatively simple genetic structure of the patellamides to generate new peptides. Their previous research had focused on one particular pathway, alterations in which they hypothesized was the origin of the diverse library of peptides found in marine ascidians. Haygood's group contributed data showing that the many symbiotic cyanobacteria strains are very closely related. Therefore, the patellamide genes are evolving unusually rapidly, suggesting they may be readily engineered to make new compounds. Encouraged by these findings, the researchers engineered a new cyclic peptide: eptidemnamide.

"The beauty of this approach," says Haygood, "is its simplicity. It's quite clear what one needs to do in order to effect a change in the resulting compound."

The ability to use this new method in the laboratory opens myriad possibilities for developing drugs to fight cancer, HIV, and other diseases, according to Eric W. Schmidt, Ph.D., assistant professor of medicinal chemistry at the University of Utah College of Pharmacy and senior author on the study.

"The promise of genes is that you can access the tremendous natural diversity of the worlds organisms to find new natural compounds for human health," Schmidt said. "You can also use genetic engineering to modify these compounds and invent new drugs to target human diseases."

Now that they've proved the concept by showing compounds can be synthesized from DNA, the researchers want to figure out how to produce greater quantities of compounds for testing and drug development. E. coli is a good producer of compounds, but yields are not yet practical.

Haygood notes that there are several possible future directions for the work, including examining new patellamides and continuing to diversify the manipulations of pathways to see how much the structure can be varied while still producing patellamides.

One student of Dr. Haygood's, now graduated, participated in the research published in Nature Chemical Biology; another is currently looking at other classes of compounds found in these ascidians.

Collaborators on the study besides Drs. Schmidt and Haygood include: Sebastian Sudek, from the Scripps Institution of Oceanography at the University of California, San Diego; M.J. Rosovitz and Jacques Ravel, both of the The Institute for Genomic Research, Rockville, Md.; Mohamed S. Donia and Brian J. Hathaway, both of the Department of Medicinal Chemistry, University of Utah College of Pharmacy.