Dr. Jeremy Wulff
Associate Professor, Department of Chemistry
Phone: (250) 721-7179
Research area: medicinal chemistry, protein-protein interactions
Chemist’s approach to pancreatic cancer leads to new compounds, surprising results
UVic chemist Dr. Jeremy Wulff began his research career with an affinity for synthesizing complex chemicals. For his PhD, for instance, he was the first to synthesize two active ingredients from the roots of Ruta chalepensis, a Saudi desert herb used as a folk remedy for arthritis and muscle spasms.
One might ask why you’d synthesize a compound from scratch, when it already exists in nature. One reason is that once you’ve created a chemical pathway to make a molecule, you have a route that can be tweaked to create modifications, ideally creating a drug that is less toxic, more potent. However, most synthetic chemists leave this follow-up work to biochemists and are content to bank their chemical structures in libraries for others to exploit.
Not Wulff. Being a synthetic chemist is a “perfectly reasonable pursuit,” he says, “But it is a little unsatisfying. At the end of the day, you put your chemical in the fridge and leave with your PhD. I wanted something a little more…holistic, I guess.”
Thus, when he went to Harvard for a post doctoral fellowship, he gravitated to the biochemists in his research group who were studying natural microbial products for drug potential and characterizing how these products work. Wulff began compiling biochemistry techniques and knowledge, so that when he began his own research group, he could choose a likely drug target to synthesize, but also follow through by testing the molecule’s effectiveness in a biological system, then tweaking the molecule’s design through new synthesis techniques, and testing again.
When he came to UVic’s chemistry department three years ago, he settled on a promising area for this approach: modulating interactions between β sheet structures in proteins from the immune system. β sheet interactions have not been broached by many researchers yet, even though this area holds the potential to tackle diseases where traditional drug design approaches have failed, starting with pancreatic cancer, a form of cancer that has the worst survival rates and the fewest options for treatment.
A little background may help explain why it is both a neglected and promising field. β sheets are well-known to biochemists; they are the second most common type of structure found in proteins (after alpha helixes). They are formed when amino acid chains fold to form sheets that are pleated and slightly twisted. They often form a binding surface where two proteins stick together. The most famous β sheets are those that glob together in a destructive fashion in the brains of Alzheimer’s patients, forming amyloid plaques. Wulff is interested in β sheets which form part of the binding surface between T-cell receptors and ligands. For instance, in one project, he is focusing on a T-cell receptor called Programmed Death 1 (PD-1), which, as its name suggests, is involved when a cell calls on the immune system for its own destruction, otherwise known as programmed cell death, or apoptosis. In T-cells, programmed cell death occurs when a worn-out T-cell overexpress PD-1 on its surfaces, which binds to the Programmed Death - Ligand 1 (PD-L1). This interaction triggers a cascade of phosphorylation signals that leads the immune system to destroy and recycle the cell.
Pancreatic tumours (as well as many other types of cancer) overexpress PD-L1, causing a wave of T-cell death as the tumour advances. There is evidence from mice studies that if you use an antibody to block the interaction between PD-1 and PD-L1, you can keep T-cells active, which then attack and contain the tumour. Given the lack of antibody-based therapies for this disease in humans (antibody therapies hold great promise, but are hard to scale up and make reproducibly) Wulff wants to try to synthesize a chemical that mimics a β sheet, inserting itself between receptor and ligand. This is easier said than done. The structural challenge involved becomes clear if you realize the relative sizes of protein surfaces to drug compounds. Using a molecule to keep two β sheets from binding together is like trying to use a piece of rice to stop the collision of two elephants (as CBR member Fraser Hof
so eloquently put it while describing his related project.)
In contrast, most of today’s drugs do not block the interaction between two proteins, but rather, block enzyme reactions or other small molecule-protein interactions. b-sheet interactions comprise a whole other subset of protein functions that has yet to be tapped for drug design. Challenges aside, Wulff hopes he is in the right time and place to open up new possibilities. Although the synthesis of the β-sheet mimetics has not yet been completed, the route has already led to a new class of compounds that are expected to act as biodegradable insect pheromones. These compounds are currently being evaluated in collaboration with insect scientists.
Likewise, while trying to synthesize a natural product (didemnaketal A) thought to disrupt the β sheet interface of HIV protease, his group developed an intriguing bicyclic sulfone molecule, which turns out to inhibit the viral neuraminidase – an important target for influenza. This variety of unexpected results and applications is likely to continue, given the prevalence of β sheets in nature and the novelty of Wulff’s approach.
Meanwhile, Wulff has almost finished optimizing an assay to screen hundreds of chemicals at a time (using fluorescent polarization) for their ability to disrupt β sheet binding. Wulff is excited by this assay– it will provide the biochemical insight needed for him to return to his chemical synthesis bench, completing a multidisciplinary circle he was missing during his PhD. Soon, he’ll use the assay to screen natural products, then modifications of natural products, or purely synthetic compounds, as his work progresses.