In the genteel game of croquet, the goal is deceptively straightforward: to hit your ball through a series of hoops before your opponent does. However, anyone who has picked up a mallet knows the sport can get downright cutthroat. A strong player with the right strategy can hit her opponent’s ball so far away that it essentially knocks him out of the game.
That’s similar to what scientists are starting to do with certain types of harmful proteins in the body. Of course, most proteins aren’t bad. Some current medicines even focus on enlisting the help of proteins that are beneficial in fighting disease. For example, activating a particular protein may help a person’s immune system, boosting her ability to fight infections or even cancer. That’s kind of like focusing on using your shot in croquet to get your ball through the hoop to score points.
But, just like croquet players trying to take their opponents out of the game by knocking their balls well out of the way, researchers are attempting to target the ‘bad’ proteins with the goal of destroying them altogether. By working with the body’s natural ability to break down proteins, called protein degradation, scientists have found another way to reduce, and in some cases, beat disease.
The Ties That Bind
Proteins work by binding to other molecules, and each protein is generally able to bind to only a few specific molecules in the body. The substance that binds to the protein is called a ligand for that protein, which comes from the Latin verb ligare, or “to bind.” When a protein binds to its ligand it starts a cascade of different actions. Most of the time, these actions are necessary for the body to function, but sometimes they can be detrimental by telling the protein to attack the body’s own cells or signaling tumor cells to grow.
Scientists have traditionally manipulated proteins in several ways in their attempt to create medicines and improve people’s health.
“Sometimes when we develop therapeutic agents we activate the function of protein, but most of the time we try to inactivate it,” says Adam Gilbert, Senior Director in Medicinal Chemistry at Pfizer’s Groton, CT site. “We've rarely been able to actually destroy a protein.” But by triggering protein degradation, scientists now have an improved way to remove specific proteins from the biological equation.
The Importance of a Knockout Shot
Why can eliminating a protein sometimes be more effective than just turning off its effects? One good example comes from attempts to treat prostate cancer. In prostate cancer, a protein called an androgen receptor gets upregulated, or, as Gilbert puts it, the protein “starts to signal like crazy and causes proliferation of tumors in the prostate.” One solution is to try to inhibit the function of androgen receptors, which can shrink the tumors for a while.
“But what happens,” says Gilbert, “is since cancer cells mutate really fast, eventually you'll get tumors that express a mutant androgen receptor so the inhibitor of androgen receptors is no longer effective and the tumors will start to metastasize again.” That means protein degradation can be a crucial way to stay one step ahead of fast-changing cancer cells.
Using the Body’s Recycling Plant
Getting rid of a problematic protein, however, isn’t easy. Since DNA and RNA contain the code for creating individual proteins, scientists long focused on these two nucleic acids as the key to purging proteins. But it’s hard to design a DNA- or RNA-based therapy for protein degradation with the ideal pharmacological properties—namely, that its effect on the body can be modified with changes in concentration and controlled over a period of time, and that the immune system doesn’t mount an unwanted response against it. So scientists had to find an easier way.
They found it by working with the body’s natural processes.
As a matter of course, the human body actually destroys proteins all the time through the proteasome degradation mechanism. The first step in the process of breaking down a protein happens when a small molecule called ubiquitin attaches to proteins in a process called ubiquitination. The enzyme that attaches the ubiquitin to a protein is called a ligase. Ubiquitination can have multiple effects on protein function. But in this case, when multiple ubiquitins get attached to a protein in a very specific pattern, it serves as a signal to a cell that it’s time to shuttle the protein to a biological complex in the cell called the proteasome.
“The proteasome is like the cellular garbage disposal,” says Gilbert. “It basically chews up the proteins back into its component amino acid parts so the cell can reuse them to build additional proteins.”
Researchers are now using this knowledge to target certain proteins for destruction by attaching signals that that kick-start proteasome degradation. “Scientists are turning this concept of breaking down proteins into practice,” says Gilbert. “Leaders in the protein degrader field are pursuing therapies based on androgen receptor or estrogen receptor knockdown. These approaches could have advantages of being more durable to known resistance mechanisms in certain types of prostate or breast cancer.”
If they are successful in marking specific proteins for destruction, scientists could kick certain diseases off the playing field — at least hopefully for a prolonged time — for future generations.