Taking Aim Against Disease

A chemist's quest to thwart the key proteins that have long been considered “undruggable”
Joshua Kritzer
“This is a great tool not only for drug discovery, but also for target discovery,” says Joshua Kritzer. “That’s still the biggest challenge for drug discovery—figuring out what to target in a cell that will be safe and effective for a given disease.” Phot
June 13, 2011

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The human body contains many thousands of different proteins, molecules that play a crucial role in almost every biological process—those that keep us living, and those that can lead to disease and death.

Yet for researchers seeking treatments for some of the most devastating illnesses, the majority of proteins in the body lie tantalizingly out of reach. These proteins—some 80 to 90 percent of them—are considered “undruggable,” meaning that current drug discovery techniques are unable to find drugs to target them.

Now a Tufts chemist has developed a technique to find substances that might target those previously unassailable proteins—it could be a giant step in developing drugs to fight cancer and other diseases.

Joshua Kritzer, an assistant professor of chemistry in the School of Arts and Sciences, knits together concepts from chemistry and genetics to screen for new drug leads. He has applied this unique approach to Parkinson’s disease and to various cancers, but he says his work potentially could be applied to drug discovery for diabetes, obesity and autoimmune diseases such as multiple sclerosis.

“Everything we do in my lab has a direct application to human disease,” says Kritzer, who received a 2010 New Innovator Award from the National Institutes of Health for his work. “In graduate school I decided to focus on human disease, and I’ve kept up that focus ever since.”

His undergraduate training in chemical engineering informs his research, too. “From my engineering background, I really have a problem-solving approach,” he says. “Engineering is building something to solve a problem, but that’s how I view science in general—I’ve used science primarily as a tool for solving problems.”

The Key to Cell Growth

Kritzer’s NIH-funded project looks specifically at a type of protein known as a transcription factor—a protein that acts as a switch that literally turns genes on and off. “If they sound like very important kinds of proteins, that’s because they are very important proteins,” Kritzer says. “Almost everything that happens in your cells is a result of turning specific genes on and off.”

These particular proteins, the transcription factors, are “very squarely in that 80 percent of proteins that are completely undruggable,” he says. They do not possess active sites, or pockets, that are the traditional bull's-eye drug developers look for. “Show a transcription factor to a medicinal chemist and he’ll say, ‘I have nothing on the shelf that can even begin to target that,’ ” Kritzer says.

Transcription factors are key to cell growth, and, as such, play an important role in the development of cancer, a disease in which cell growth goes awry. While there are scores of genes in each cell that regulate the various aspects of cell growth, they are all controlled by just a handful of transcription factors. Kritzer likens the transcription factors to an air traffic controller who determines when and where planes should be landing and taking off.

Right now, drug developers can only do the equivalent of diverting individual planes, rather than funneling information through an air traffic controller who’s in direct control of many planes at once. If they could find substances that would affect the transcription factors, they could gain control of the overall cellular growth program instead of just individual aspects of it.

“If we could target transcription factors, we would have very broad-acting anti-cancer compounds,” says Kritzer. But because of the structural composition of the transcription factors, they don’t respond to traditional cancer drugs—hence, the “undruggable” label.

The Little Switch

To overcome this obstacle, Kritzer’s lab is working with compounds known as cyclic peptides, which are, in essence, little snippets of proteins. The hope is to discover a cyclic peptide that can interact with the transcription factors.

The idea of focusing on cyclic peptides is not unique to Kritzer’s lab. But he has taken an innovative approach on two fronts: creating large quantities of cyclic peptides using baker’s yeast, and devising a way to quickly identify those cyclic peptides with disease-fighting potential.

His first trick, as he calls it, is to develop a system for creating millions of different cyclic peptides at once. To do this, he and the researchers in his lab use yeast cells—the same yeast that is used by bakers and brewers to make bread and beer. “Yeast has been a genetic model for almost every human disease over the last 60 years,” Kritzer says. “It’s been the go-to organism for testing ideas about biology. Humans share more with yeast than you might think.”

Instructions for making the cyclic peptides are genetically programmed into the yeast, and each yeast cell becomes a cyclic peptide manufacturing plant.

“This has enabled us to make thousands of times more cyclic peptides than if we had to synthesize them one by one,” Kritzer says. “The yeast makes the compounds for us, and we can sift through 5 million in a week,” he says, looking for those that have properties that might make them good candidates for further exploration.

Kritzer’s second “trick” is to start with strains of yeast that have already been developed to model human diseases such as cancer. By using strains that are already genetically programmed to die from the disease, he can challenge them to use some of the cyclic peptides to survive.

“There will be 5 million yeast cells on the plate, and they will all die, except maybe one or two that happen to be making a cyclic peptide that saves them,” Kritzer says. “So not only do the yeast make 5 million compounds at a time, but they can tell me which of those 5 million are interesting ones.” Those compounds can then be used for more testing as potential therapeutic agents that target those all-important undruggable transcription factors.

“If we find a peptide that targets a transcription factor, that’s not going to become a drug overnight,” Kritzer says. “But just proving you can target transcription factors—that is a coup in and of itself. You’ve shown they are not undruggable.

“This is a great tool not only for drug discovery, but also for target discovery,” he says. “That’s still the biggest challenge for drug discovery—figuring out what to target in a cell that will be safe and effective for a given disease.”

 

Helene Ragovin can be reached at helene.ragovin@tufts.edu.