New hope for stroke treatment: dipeptide molecules that enhance the activity of brain peptidase neurolysin Nln

Ischemic stroke is the second leading cause of death in the world-when the blood vessels leading to the brain are blocked, the blood flow to the brain is reduced and the brain loses its vital supply of oxygen and nutrients

In recent years, some progress has been made in understanding the signaling pathways related to the brain's self-protection mechanism, enabling researchers to identify new potential targets for in-depth research

In previous studies, Karamyan’s laboratory discovered for the first time that Nln is a key endopeptidase.

Karamyan’s recent collaborative research is a continuation of his previous work to evaluate the potential of Nln as a target for stroke treatment by searching for small molecules that can enhance the activity and catalytic efficiency of Nln

We know from experience that it is difficult to improve the activity of enzymes

This summer, the Karamyan research team and the University of Florida collaborator David Ostrov discovered two histidine dipeptides that can selectively enhance the activity of neurolysin ("identify and characterize two structurally related dipeptides, improve neuro The catalytic efficiency of lysin," published in the August 13th issue of the Journal of Pharmacology and Experimental Therapy)

"We screened tens of thousands of compounds on the computer and ranked them based on their likelihood of interacting with neurolysin," Karamyan concluded

The next step is to determine how to use these neurolysin histidine dipeptide activators to improve the prognosis of stroke

Since the target organ is the brain, Karamyan said, he also needs to consider whether the peptide activator can pass through the blood-brain barrier-the blood-brain barrier is the barrier between the brain and other parts of the body

In order to solve these problems, the Karamyan laboratory cooperated with the Abbruscato laboratory, which specializes in the blood-brain barrier, and the Trippier laboratory, which specializes in medicinal chemistry

Every time Trippier finishes modifying a molecule, Karamyan's laboratory must confirm that the molecule can still activate neurolysin Nln and enhance its activity while remaining stable

Karamyan said: "We tried to design and develop better high potency molecules, which means that only requires less compound to enhance the activity of nerve lysin

The study identified three molecules, which showed a more significant improvement compared to the original dipeptide—retaining the pharmacodynamic histidine portion and having a micromolar potency that was more than 40 times higher

Karamyan believes that the achievements he and his collaborators have achieved represent a huge advancement-including the understanding of neurolysin as an enzyme and the molecules that are expected to be used in the treatment of stroke and other neurological diseases in the future