Discovery opens new avenues to design drugs to fight drug-resistant malaria

For the first time, UBC researchers have shown a key difference in the three-dimensional structures of a key metabolic enzyme in the parasite that causes malaria compared to its human counterpart.

The finding, recently published in the International Union of Crystallography Magazine, takes researchers one step closer to developing new therapies to fight drug-resistant malaria.

The structural differences in the metabolic enzyme, known as hexokinase, were captured by cryogenic electron microscopy or cryo EM, whereby the samples are cooled to cryogenic temperatures and examined to near-atomic resolution.

The researchers found that the enzyme in the malaria-causing parasite, known as Plasmodium, takes a form that has four individual subunits, while the enzyme in humans takes a form with only two subunits. This difference provides a unique opportunity to design drugs that specifically target the Plasmodium enzyme, without affecting the human version.

“Our new findings offer the possibility of designing antimalarial drugs that selectively target the unique structure of parasite-infected cells, especially in the early stages of infection. Think of it as cutting a key based on the shape of the eye of the lock”. says the study’s lead author, Dr. Sriram Subramaniam, President of Research for Excellence Gobind Khorana Canada at UBC School of Medicine.

According to the World Health Organization, malaria, a mosquito-borne disease, affects more than 200 million people annually, resulting in the deaths of approximately 400,000 each year. New treatments are needed as resistance to the most common forms of antimalarial drugs is on the rise, making the disease increasingly difficult to treat in some parts of the world.

“With this discovery, a new avenue was opened to combat drug-resistant malaria,” says first study author Dr. Shanti Swaroop Srivastava, a UBC postdoctoral fellow in Subramaniam’s laboratory, who is recognized for her world leading contributions to cryo EM. “Now that we know the atomic structural information for this key metabolic enzyme, new drugs can be developed to block the parasite’s ability to metabolize glucose and survive.”

The study, conducted in Dr. Subramaniam’s laboratory, was conducted in collaboration with research groups at Clemson University, led by Dr. James Morris, professor of genetics and biochemistry, and the Ohio State University Medical Center. , chaired by Dr. Mark Drew, professor of microbial infection and immunity.