UF researcher finds way to boost protective brain enzyme after stroke

GAINESVILLE, Fla. — In the race to limit brain damage after a stroke, most treatments try to block harmful processes. A University of Florida Health researcher is pursuing a different strategy: boosting the brain’s own protective machinery.

Using the University of Florida’s HiPerGator supercomputer, a UF Health researcher helped identify a drug candidate that enhances an enzyme known to curb cell damage after an ischemic stroke, which occurs when a clot blocks blood flow to the brain.

Such drug candidates could eventually serve as the foundation for new stroke therapies.

The researcher’s study, published recently in the Journal of Pharmacology and Experimental Therapeutics, includes collaborators from Texas Tech University and other institutions.

The study’s key discovery was enabled by the UF HiPerGator Drug Discovery Platform, developed by UF Health structural biologist and immunologist David Ostrov, Ph.D. It is a complex computer program, aided by artificial intelligence and large-scale computing, that can predict how chemical compounds bind to enzymes and enhance their beneficial activity.

This strategy differs from traditional drug-discovery methods. Many medicines work by inhibiting enzymes or other proteins that contribute to disease. A class of medications called ACE inhibitors, for example, treats high blood pressure by blocking a chemical that makes blood vessels tighten.

Developing drugs that shut down harmful proteins is easier than boosting protective properties in an enzyme that is beneficial, Ostrov said.

Enzymes are proteins that trigger the chemical reactions necessary for life. Across the trillions of cells in the human body, they enable the countless reactions that keep the body functioning. Digestion, for example, relies on enzymes.

“You have to find a novel way to do it because there’s no cookbook for enhancing an enzyme’s activity,” said Ostrov, an associate professor in the UF College of Medicine’s Department of Pathology, Immunology and Laboratory Medicine.

The study focused on an enzyme called neurolysin, which is released in the brain after an ischemic stroke. It helps reduce cell damage, swelling and inflammation in brain tissue.

“When enzymes do a good thing, sometimes you want them to do more of a good thing,” Ostrov said.

Ostrov used HiPerGator to screen 139,735 compounds to identify those that might best enhance neurolysin’s protective benefits. The most promising were tested in the laboratory for their effectiveness.

Ostrov’s platform searches for sites on the enzyme where a compound might attach, or bind. It doesn’t look at an enzyme’s primary working site. That’s the place where its main chemical reactions are initiated. It instead looks for other “structural pockets” that subtly influence how the enzyme moves and functions.

“It’s like greasing the wheel, making the car run faster,” Ostrov said.

Researchers identified one compound that worked exceptionally well: a pyridine-piperazine derivative. This molecule enhanced neurolysin’s activity, enabling it to act more quickly.

The compound is more promising than earlier chemicals the team identified, Ostrov said, because it might be more suitable for oral dosing and longer lasting in the body. Those traits make it more useful as a medication.

The study’s senior researcher, Vardan T. Karamyan, Pharm.D., Ph.D., a professor of pharmaceutical sciences at Texas Tech, invited Ostrov to join the study because of the UF researcher’s success using HiPerGator to screen large libraries of drug candidates.

“The door has opened to new strategies in drug discovery,” Ostrov said. “If an enzyme has beneficial effects but isn’t working at full capacity, we may now be able to enhance it rather than block it. This approach is rapid, cost-effective and could be applied to many different diseases.”