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Technology & Innovation

Bioengineering – Using Nature’s Catalysts in Drug Development

Armstrong Atlantic State University

10/26/2009 - Chemistry students at Armstrong Atlantic State University (AASU) are engaged in biocatalysis research thanks to Brent Feske, AASU assistant professor of chemistry, and recent funding from the National Science Foundation (NSF). Biocatalysis, a subfield of bioengineering that uses nature’s catalysts to advance the production of useful pharmaceuticals, is experiencing rapid growth. This column presents a brief history of biocatalysis and its role in drug development.

Catalysts are specialized molecules that speed up the rate of chemical reactions. Most catalysts in living organisms are enzymes, or large proteins. Without enzyme catalysts in our bodies, we would never be able to digest our food quick enough to survive. Enzymes are essential to all living organisms, from the smallest bacteria to the largest whale.

Small molecules derived from living organisms are referred to as “natural products” in the scientific community. Natural products are most popular and significant because of their pharmacological activity. As of 2002, more than 50 percent of all drugs ever used were natural products or derived from a natural product. Drug discovery has often focused on naturally occurring compounds. In 1960, the National Cancer Institute established a program that purified natural products from biological samples collected from the rainforest and other parts of the world and screened the compounds for their pharmaceutical activity. This program was accelerated by the early success of the antileukemic agents vinblastine and vincristine, which were both extracted from periwinkle leaves found in Madagascar. Throughout this program’s 22-year tenure, two more compounds were found, Taxol and camptothecin, which showed medicinal potential in the fight against cancer.

Taxol was isolated from the bark of the Pacific yew tree and shown to have anti-tumor activity in 1962. Though promising, Taxol was a relatively large compound that was highly insoluble in water, which made it nearly impossible to deliver to patients. In addition, as laboratory testing continued on Taxol, the supply of Pacific yew trees, a very slow-growing tree, was diminishing.  As a result, the hope that Taxol would be an effective and administrable cancer drug diminished.

Nearly 15 years later, Dr. Susan Horwitz of the Albert Einstein College of Medicine completed a series of detailed studies on this potential drug. She found that Taxol’s mode of action was completely different than any other cancer drug thus it had the potential to revolutionize chemotherapy. These exciting results propelled Taxol through clinical trials. In 1992 it was approved for the treatment of breast and ovarian cancer. This led to a fundamental problem: because of harvesting to extract Taxol, the Pacific yew trees were on the brink of extinction.

Chemists were given the task of developing what would soon become the largest selling cancer drug ever placed on the pharmaceutical market, yielding sales in the billions of dollars. It would be up to chemists to use synthesis, which is the technique of cleverly combining smaller molecules in a series of steps to create larger ones.

Fortunately, chemists were paying attention to the discovery of this new drug, and total synthesis began in the 1980s. Unfortunately, total synthesis from scratch was a daunting task because of the large and complicated structure of Taxol. So, a new approach had to be found.

Interestingly, Dr. Pierre Potier of the French School of Natural Products and colleagues discovered the complex ring structure of Taxol in the Pacific yew bush. This was attractive because one would only need to attach the Taxol “side chain” to this ring structure to produce the drug.More importantly, this compound was renewable because it is found in the leaves of the Pacific yew bush, which can be harvested without killing the plant. This novel strategy resulted in a new synthetic challenge to synthesize the Taxol side chain in the most economical and efficient way.

Chemists have been creative in answering this call by developing a variety of approaches to the Taxol side chain. Andrew Greene of the University of Science, Technology and Medicine at Grenoble, France, and colleagues developed the first side chain synthesis in 1986, but it did not meet the FDA's purity standards. Soon after, Robert Holton at Florida State University (FSU) patented his synthesis in 1989 with Bristol-Myers Squibb, and production began in the early 1990s. Since this patent date, Holton and FSU have earned over $200 million combined.

Further, in 2005, Brent Feske and colleagues at the University of Florida developed one of the shortest overall routes to the Taxol side chain using biocatalysis as the key step.

There are two fundamental advantages to biocatalysis, which both lead to financial gain. First, enzymes are very efficient; thus they yield a very pure and specific product, minimizing waste. Second, since enzymes are proteins, they are very safe to work with, and it is affordable to dispose of the water/protein reaction solution once the reaction is finished.
So the logical question is: Why aren’t pharmaceuticals more commonly synthesized by biocatalysis? The simple answer is that historically, obtaining large amounts of pure enzyme was very difficult and expensive. However, with recent advancements in the technology of molecular biology and our ability to engineer organisms, this has become a more viable approach.

Feske moved to AASU in 2005, where the NSF has funded his biocatalysis research, enabling him to continue to investigate ways to utilize these systems towards pharmaceuticals. In 2007, he reported how this system can be used to make Prozac and other serotonin reuptake inhibitors by means of biocatalysis. He is currently having success in the synthesis of the antibiotic Fosfomycin. AASU undergraduate students working in Feske’s laboratory have the exciting opportunity to work on this NSF-funded project.

George Shields is the dean of the College of Science and Technology at Armstrong Atlantic State University.  He can be reached at This email address is being protected from spambots. You need JavaScript enabled to view it.. Brent Feske is an assistant professor of chemistry in the Department of Chemistry & Physics, in the College of Science and Technology, at Armstrong Atlantic State University.  He can be reached at This email address is being protected from spambots. You need JavaScript enabled to view it..

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