Baker's yeast to aid drug development

Even with cutting-edge technology, it can take years to untangle how drugs interfere with cells. In fact, one of the hardest parts of drug discovery is pinning down how a medicine actually works in the body.

For example, it took nearly 100 years to uncover the molecular target of aspirin. But to develop medicine that targets disease effectively and is safe – with no side-effects – these molecular insights are key.

The study, published in the journal Nature Chemical Biology, tested how nearly 14,000 compounds, hundreds of which were previously unexplored, affect basic cellular processes so drug makers can become aware of chemicals that are most likely to target a particular disease.

The data pointed to about 1000 chemicals, many of which are natural products derived from soil microbes as a rich source of potential drugs against a range of diseases, from infections to Alzheimer’s and cancer.

The research teams led by Charles Boone, a professor of molecular genetics at U of T’s Donnelly Centre for Cellular and Biomolecular Research, Chad Myers of the University of Minnesota-Twin Cities and Professors Minoru Yoshida and Hiroyuki Osada from the RIKEN Centre for Sustainable Resource Science in Japan developed a new chemical genetics approach to link a drug to a cellular process it acts on.

Boone and Myers are also fellows at the Canadian Institute for Advanced Research where Boone is a senior fellow and co-director of the Genetics Networks program.

Despite modern technology, drug discovery still largely rests on guesswork. To find a drug that kills cancer cells, scientists sift through libraries containing thousands of chemical compounds, the majority of which will have no effect at all.

“There are many different types of libraries to choose from. A lot of the time you choose a library based on its availability or its cost, not any sort of functional information, and so it becomes a shot in the dark,” says Jeff Piotrowski, a lead author on the paper who was a postdoctoral researcher in both the Yoshida and Boone labs and now works at the Boston biotechnology company, Yumanity Therapeutics, which uses yeast cells to find drugs for neurodegenerative diseases.

With their chemical genetics platform, Piotrowski and colleagues were able to show which parts of the cell are targeted by thousands of compounds from seven different libraries, six of which have been extensively explored and includes collections from the National Cancer Institute (NCI), the National Institute of Health and the pharmaceutical company GlaxoSmithKline. The seventh and largest collection, from RIKEN in Japan, harbours thousands of virtually unexplored natural products from soil microbes.

“By annotating these libraries, we can tell which library targets which bioprocess in the cell. It gives us a head start on linking a compound to a target, which is perhaps the most challenging part of drug discovery,” says Piotrowski.

The data revealed, for example, that the RIKEN library contains compounds that act in many different ways: from microbe-fighting chemicals that could be used to treat infections to drugs that target cellular trafficking in Alzheimer’s and Parkinson’s diseases, to those that interfere with cell replication and might be used against cancer. In fact, the RIKEN library turned out to have many novel compounds with anti-cancer potential.

“It’s long been thought that natural products are more functionally diverse, that they can do more things than purely synthetised compounds and that certainly seems to be true from our data,” says Boone.

And because natural compounds were shaped by evolution to act on living organisms, they are better candidates for future drugs than synthetic compounds that often do not even get into the cells. For example, aspirin, penicillin and the cancer drug taxol come from nature.

The data also revealed chemicals that influence more than one process in the cell. These compounds are more likely to cause side-effects and are best avoided. “With our map, we can see these promiscuous compounds earlier and focus on the good ones,” says Piotrowski.

The study was possible thanks to earlier research by Boone, Myers, and Donnelly Centre Director Brenda Andrews, which mapped out how thousands of genes interact with each other to drive fundamental processes in the cell.