Hardy receives $825k grant to study proteins that cause cell death

Jeanne Hardy has received a five-year, $825,000 grant from the National Institutes of Health to unlock the secrets of a group of proteins called the executioner caspases, which control cell death and play a role in cancer, strokes, Alzheimer’s and Parkinson’s disease. The heart of the grant is identifying the precise role of each caspase, which could lead to the development of new drugs to treat these diseases.

“Blocking cell death, known as apoptosis, is a useful way of treating cells that are routed to death following heart attacks and strokes, or in long term diseases such as Alzheimer’s,” says Hardy, an assistant professor of Chemistry. “On the other hand, activating cell death is an effective way to kill cancer cells, and many of the best-known cancer therapies work via this mechanism.”

Determining the action of a single protein is difficult in a closely related family like the executioner caspases, since molecules that can bind to the proteins and block their action work equally well on each member of the group. Hardy will solve this problem by changing the structure of each caspase, creating unique sites on each protein that can be blocked by an existing drug of her choice.

“Each caspase has active sites on the outside of the molecule and an inner pocket called an allosteric site, which are similar for each of the 12 proteins,” says Hardy. “We will redesign the allosteric site in each caspase to react to an existing drug, creating a switch that lets us turn them on or off. Because none of the family members will contain the same designed allosteric site, they will be unaffected by the existing drug.

By analyzing what happens to the chemistry of a cell after inactivating each caspase, Hardy will be able to determine exactly which proteins are cleaved by a particular caspase, and whether blocking that protein could be useful in treating a particular disease. “We should be able to tell whether activating a certain caspase can induce death in cancer cells, and whether activating a different caspase results in cell death associated with Parkinson’s disease.

Hardy’s method could eventually be used to study the action of the 40,000 proteins in the human body. “Because we have the sequence of the human genome, we understand what these protein building blocks are, but we still don’t fully understand what each of them does,” says Hardy. “As a result, drugs are developed to target less than 1 percent of these proteins, and medications usually target more than one type of protein, which can cause unwanted side effects, such as nausea and hair loss in cancer patients on chemotherapy.”

According to Hardy, drugs usually bind to proteins at cavities called active sites, and finding a drug that is specific for that site is a trial and error process that can take 10 to 20 years and cost hundreds of millions of dollars.

Hardy’s work on allosteric switches will provide a way that just one protein, but no other, can be blocked by an existing drug, providing a direct and rapid means of determining whether inactivating that protein could cure a particular disease, such as cancer, strokes, heart attacks and Alzheimer’s.

This method also has another advantage over existing technology. “Turning off a protein using an allosteric switch gives you the same result as treating with a drug, since the protein is still present in the cell, but is in an inactive form,” says Hardy. “Knocking out a protein at the genetic level means that the protein is completely gone from the cell, which often doesn’t give the same response as simply blocking the action of a protein.”

April 30, 2008.

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