Nav: Home

Cancer: Faster drug discovery to hit 'undruggable' targets

January 20, 2020

ANN ARBOR--Medicines made from coiled protein fragments could provide a new handle on hard-to-treat diseases like cancer, but they are difficult to design. But a new technique, developed at the University of Michigan, could change that.

It can harness bacteria to produce billions of different drug candidates that won't fall apart quickly inside the body.

Some advanced cancer medications target cancer cells with immune markers that latch onto the outsides of the cancer cells, for instance. But these immune markers are large, operating between cells rather than inside them. To disrupt cancer cells from within, the medicine must be small enough to get into the cell.

However, ordinary small-molecule medications can't hit messenger proteins with smooth surfaces. A new type of medication is needed.

"It's a Goldilocks principle," said Greg Thurber, U-M associate professor of chemical engineering, who led the work. "The drug has to be small enough to get into cells but large enough to grab onto proteins inside cells that don't interact with ordinary small-molecule drugs."

Protein fragments, known as peptides, could fill this gap. They are small enough to slip inside cells but complex enough to bind with smooth proteins.

One example of an "undruggable" target is MDM2, a protein that sidelines another protein known as the "guardian of the genome." This guardian, known as p53, stops cell division when genetic mutations arise, buying time for DNA repair. It can also initiate self-destruction if the genome is in bad shape. It is our front-line cancer defense.

However, cancer cells fight back by overproducing p53's inhibitor, MDM2, which binds to p53 and prevents it from doing its job. But if something intercepts the MDM2 before it ties up the p53, the cancer cells might do everyone a favor and self-destruct.

This is just one of therapies that might be possible with peptides. And the U-M team has developed a way to design them. The key innovation is how Thurber's team stabilized the peptides, which are prone to falling apart in complex environments like the human body.

"The peptide is like a Slinky, but you tie together links so it doesn't stretch out. That's what we do chemically," said Thurber.

The tie enables different drug candidate peptides to be built with bacteria as opposed to using simpler organisms, such as phages--which are essentially viruses for bacteria. Phages make only five peptides at a time, rather than the 10,000 or so that bacteria can make.

The peptides on bacteria are so plentiful that researchers can see how well they work right on the bacterium. In contrast, the phage method requires additional labor-intensive steps to find out how well peptides bind and whether they fall apart easily.

Thurber's team used E. coli bacteria to build hundreds of millions of peptides with random variations, looking for the one that was best at binding MDM2. The instructions for the peptides were written into rings of genetic code that the researchers slipped into the bacteria, causing the bacteria to produce the peptides on their cell membranes.

The ties were made from synthetic molecules that the bacteria swapped in for a peptide building block that they couldn't produce. Unlike earlier ties incorporated into phage-built peptides, the synthetic molecules won't bind to other molecules in and around the bacteria. It's an example of "click chemistry," tidy enclaves in the messy world of organic chemistry in which molecules reliably react together but are otherwise inert.

"The problem was that the reaction to tie the coils together killed the bacteria," said Tejas Navaratna, a Ph.D. student in chemical engineering at U-M and first author of the study in the Journal of the American Chemical Society. "We spent months trying to optimize the reaction so that the bacteria survived, but we eventually realized we'd have to extract the DNA that coded our best peptides and add it to fresh, live bacteria."

Each bacterium produced a different peptide, enabling the team to test hundreds of millions of different designs. To find out whether the peptides worked, the researchers mixed MDM2--attached to fluorescent molecules--in with the bacteria. The cells that lit up were producing a potentially useful drug.

While this technique is especially attractive for finding new cancer drugs, coiled peptides are under exploration for managing diabetes and HIV. The main challenge is getting the peptides into cells, which is a problem that Thurber's team is currently pursuing.
-end-
The study was funded by the National Science Foundation and the National Institutes of Health.

Study: Directed Evolution Using Stabilized Bacterial Peptide Display

Greg Thurber

University of Michigan

Related Cancer Articles:

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.
Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.
Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.