Tomorrow's Health, Today's Research

Fraser Hof

Associate Professor, Department of Chemistry
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Phone: (250) 721-7193
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Research area: the intersection of supramolecular and medicinal chemistry
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Research Profile

The promise of synthetic molecules for controlling proteins

Protein-protein binding events are at the heart of almost all biological processes. However, the list of chemicals that prevent protein-protein interactions is short. Synthesizing such agents is a promising new approach to drug development against numerous diseases, but it is a larger problem than you might think, says Dr. Fraser Hof. Nevertheless, that is exactly what his team of postdoctoral fellows and graduate students in UVic’s Chemistry Department is setting out to do.

Hof is a synthetic chemist involved in several collaborations with molecular biologists who want tailor-made molecules to interact with proteins. Among his projects, Hof is developing molecules to interrupt cell signaling pathways for cancer research; disrupt binding of infectious agents to host cells; and interact with histones to affect gene regulation, just to mention a few.

It is a Herculean task. Hof recently heard this analogy to describe how hard it is to chemically inhibit the binding of two proteins: “It is like taping a piece of rice to an elephant to keep it from running into another elephant.” The analogy is apt because the molecules that chemists build are so small compared to proteins.

Another challenge is that the ground work has yet to be done. A lot of the basic chemistry needed to tape the rice has not been carried out in biological conditions of a salty aqueous solution at 37 oC, and thus, Hof’s group don’t even have a set of rules for how synthetic molecules act in these conditions.

To understand the challenges involved, consider Hof’s experience designing a molecule to interact with histones. (To read more about the significance of histones, which are proteins that package DNA, read CBR’s Dr. Juan Ausio’s research profile).

A year ago, Hof’s group managed to design an aromatic molecule that binds to a single trimethylated lysine in saline solution at 37 oC. This was an important first step because trimethylated lysine is a form of the amino acid lysine that acts like a gene regulation tag in histones. (The presence of methyl groups triggers proteins to associate with histones, and depending on the histone, results in a section of DNA becoming either unpacked for gene expression or repackaged for gene silencing.)

“This hadn’t been done before,” Hof said, describing this first step. “But it was still only binding to an orphaned amino acid. No biochemist in the world would be interested in that – just a disembodied amino acid.”

Indeed, a biochemist working with histones would be looking for a molecule that could bind to trimethylated lysine in a complete and folded histone, and furthermore, bind only to specific trimethylated lysine in one class of histone, none others. Not to mention, of course, the molecule would have to bind so strongly, it disrupted the natural function of the protein, coming back to rice sticking to the elephant.

A year later, Hof’s team now understands some of the rules that govern such binding, and recently, he and his graduate students managed to tweak the molecule so it binds specifically to trimethylated lysine on histones. Better yet, in initial results, his team found the molecule disrupted a histone interaction known to be involved in gene regulation.

The promise of manipulating histone function has not gone unnoticed by CBR researchers Dr. Juan Ausio and Dr. Caren Helbing, who both work with histone gene regulation and have begun to collaborate with Hof. Altering histone regulation has many potential applications, such as the treatment of developmental illnesses, the treatment of a variety of cancers, and perhaps even the creation of stem cells from normal cells.

Beyond binding histones, Hof feels his work is important because it has begun to lay down the ground work to make it easier to design other medically useful molecules. His team is working on developing molecules to bind to several other modified amino acids, which commonly act as tags for biological systems. “We are really developing a new technology platform,” Hof described.