Hitting the Brakes on Dangerous Inflammation

Drs. Paul Shapiro and Jeffrey Hasday want to stop dangerous inflammation

Could a new class of drugs rebalance the body and prevent excessive inflammation?

When the body has been injured or is under attack from disease or other stressors, an important balancing act takes place. Pain, swelling, heat, and redness are often signs the body is responding to stop any immediate damage and begin the healing process. Sometimes, inflammation can become chronic and work against the body, harming healthy tissue and possibly triggering diseases including heart disease, diabetes, rheumatoid arthritis, and even some forms of cancer. A natural anti-inflammatory response usually kicks in to prevent these harmful effects, but sometimes persistent infection, environmental factors, or autoimmune diseases prevent the body from hitting the brakes on inflammation.

Paul Shapiro, PhD, professor at the University of Maryland School of Pharmacy and partner Jeffrey Hasday, MD, professor at the University of Maryland School of Medicine are developing a class of drugs that may be able to reset the natural balance of inflammation and prevent a number of serious diseases. The secret is protein kinases, enzymes that regulate how various proteins interact and alter how they function.

“Right now we're looking at it in the acute respiratory distress syndrome,” says Hasday, “which is a problem where you have injury to both lungs, requiring a mechanical ventilator often and has a fairly high mortality.” The team hopes to modify treatments to work with other medical issues, such as traumatic brain injury, rheumatoid arthritis, and inflammatory bowel disease.

Watch and listen to questions and answers with Drs. Shapiro and Hasday or read the interview transcript here.

Questions

Question: What is the focus of your research?

Protein kinases are these fascinating enzymes that change the structure and function of other proteins and they cause those proteins to have all sorts of biological effects. They're involved in every physiological function. They have hundreds of different substrates and they're over-activated in disease states and so the whole idea is, can you modulate that over-activity and alleviate the disease?

Question: How did you get to where you are today in your research?

Paul has been working on an approach of targeting the modifying activity of kinases called ERK, ERK 1, and ERK 2, and presented that work. And you've been doing that for a few years and presented that work at a seminar series that we have called the Inflammation Research Group meeting. And I have been interested in lung injury for a long time and inflammation and what causes it.

And there's a similar molecule to ERK called P38, sort of in the same family. And after the seminar where Paul presented his work on ERK, I said, you know, I think we may have another target we want to look at and that's where we got the idea to target P38 in the same way. And so that all started in about 2014, I think.

And by 2016, with the help of Alex Mackerel and the Center for Computer Drug Design, we had our first our first compound, which was one that was a commercially available small compound wouldn't be used for anything but it seemed to prevent lung injury in mice and that that's what got us started.

Question: What are you working on right now?

Right now we're looking at the acute respiratory distress syndrome, which is a problem where you have injury to both lungs, requiring mechanical ventilator often and has a fairly high mortality. There aren't any real pharmacologic agents that work yet. There's only a couple of things we know that helps. So, it's really a disease in the need of pharmacologic agents. We're also looking at a traumatic brain injury, more chronically, it may be playing a role in the muscular dystrophy. And we're also possibly in rheumatoid arthritis, chronic inflammatory disorders as well, rheumatoid arthritis, inflammatory bowel disease. These are all sort of on the on the list of what I think we want to look at because it's such the central player, the P38, is it's involved in all these diseases.