Biology may provide just the right chemistry for new drugs

NORTH BETHESDA, Md. — Chemists are struggling to develop new drugs these days — and biologists may have just the pill for that.

By tapping natural enzymes and tweaking microbes, researchers may find and make new drugs more easily, says biological engineer Vikramaditya Yadav of the University of British Columbia in Vancouver. Yadav says he has developed a method to make a complicated anticancer drug using plant enzymes and E. coli bacteria, a process he has dubbed “biosynthonics.” He presented his work July 15 at the Green Chemistry & Engineering Conference.

Although microbes and enzymes are sometimes used as tools in drug making, conventional methods rely on painstaking multistep chemical screens and reactions. Yadav’s biology-focused strategy, which he says can speed and simplify drug development, is now turning heads in the field.

“I really think he’s a visionary,” says John Tucker, a senior scientist at the pharmaceutical company Amgen, based in Thousand Oaks, Calif. “He’s kind of bridging that gap between biology and chemistry and engineering.”

Pharmaceutical companies are eager to find fresh ideas, Tucker says. In the last decade, the number of new drugs approved by the U.S. Food and Drug Administration each year has practically flatlined; meanwhile, the cost of research and development has doubled. It now takes on average more than $1 billion and 10 years to get a new drug ready to go to market.

Yadav thinks a solution to these problems will come from recent advances outside the pharmaceutical realm. He points to methods to cheaply decode an organism’s entire genetic blueprint and powerful new computer programs that simulate how biological molecules work. Researchers can now mine the genetic instruction manuals of thousands of creatures to find the codes for untapped enzymes. Using computer programs, the researchers can figure out how those enzymes trigger chemical reactions and transform biochemicals. Then it’s possible to cheaply and easily engineer microbes to use those enzymes to spit out chemicals, Yadav says.

Evolution has already tailored those chemicals to do useful things, Yadav says. For instance, the antibiotic penicillin exists so that fungi can battle bacteria.

To show that biosynthonics can work, Yadav set out to make paclitaxel, an anticancer drug made by the Pacific yew tree (Taxus brevifolia). To get enough for a single dose of the drug naturally, researchers would have to grow six yew trees for about 200 years. To make it in a lab from scratch, chemists perform 51 separate reaction steps.

But by sticking eight yew tree enzymes into E. coli, Yadav has designed a way to make a precursor to paclitaxel in one quick-growing batch of the bacteria. That precursor has the basic structure of the potent drug, like the base model of a car. Then, like tricking out that car, researchers can use simple chemical reactions to add accessory compounds to the molecule that help the drug function, creating a finished version, Yadav says. The whole process takes just 17 steps.

Researchers across the pharmaceutical industry are taking note of the strategy, says Leanna Shuster, a chemist at GlaxoSmithKline, based in Collegeville, Pa. It hasn’t been adopted yet, but “it’s most certainly being looked at very seriously,” she says.