Scientists have identified a new class of compounds capable of partially clearing the tropical parasite that causes Chagas disease out of mice, suggesting the molecular group could serve as a source of new treatments for one of the deadliest parasitic infections in the world.
The compounds are called quinazolines and are made of two conjoined rings, a benzene ring and a pyrimidine ring. The lead quinazoline, called DMU759, reduced the number of parasites in the blood of infected mice by 81%.
The results were published in Science Translational Medicine on July 9.
While the compounds are active against the parasite, they don’t last long enough in the body to make effective drugs for humans, Susan Wyllie, Ph.D., a biochemist at the University of Dundee in Scotland and the senior author of the study, told Fierce Biotech.
Wyllie’s collaborator Avninder Bhambra, Ph.D., a biological chemist at De Montfort University in Leicester, England, is now working to tweak the quinazolines to make them more stable and druglike, Wyllie said. Bhambra’s group initially developed the compounds and found them able to kill disease-causing parasites, which led them to tap Wyllie’s team to unravel how the quinazolines were achieving their deadly effect.
Chagas disease is caused by the protozoan Trypanosoma cruzi and infects about seven million people around the globe annually, mostly in Latin America, killing more than 10,000 every year. Infection leads to symptoms like fever, headache, difficulty breathing and chest pain. The two approved treatments for the disease cause intense side effects, and about 30% of survivors develop a currently untreatable chronic form of the malady that causes heart disease and an enlarged digestive system.
The toxicity of the approved drugs “is so severe that in most cases, people can't complete the treatment regimens,” Wyllie said, adding that both drugs aren’t very effective at treating the chronic stage of Chagas disease. “This is why we need to desperately find new treatments.”
Chagas disease is also often underdiagnosed, Wyllie said, because its initial symptoms mimic those of a typical cold or flu and there can be a long asymptomatic lull between its acute and chronic stages. The disease could also increase in prevalence as global warming is predicted to allow T. cruzi’s primary vector, insects commonly called kissing bugs, to expand northward.
Wyllie’s team is guns for hire, hunting down targets for neglected tropical diseases on behalf of drug developers. To ID the molecule that the quinazolines bind to, they first used a technique they call an overexpression library—they grew many different populations of a related parasite, each with a different gene tweaked to produce more of its protein than usual.
Heaping quinazolines onto these modified parasites allowed the researchers to see which no longer succumbed to its toxic effects and finger the gene responsible, which codes for an enzyme called lysyl-tRNA synthetase.
This enzyme is critical for the parasite to make proteins, Lindsay Tulloch, Ph.D., a biomedical scientist in Wyllie’s group and lead author of the study, told Fierce Biotech. “It's loading the lysine onto tRNA so that it can then go into the developing protein during protein synthesis,” he said.
Without lysyl-tRNA synthetase, the parasites can’t incorporate lysine, one of the most common amino acids, into their proteins, which causes protein synthesis to “essentially grind to a halt,” Wyllie explained.
Further analyses confirmed that DMU759 binds to this enzyme not only in T. brucei, which causes sleeping sickness, but in Chagas-causing T. cruzi as well.
“We decided to focus the work at that point on T. cruzi because of this unmet need” in Chagas disease, Wyllie explained.
With the quinazolines now back in Bhambra’s hands, Wyllie and her crew of target hunters are turning their attention to more complex pathogens. Current projects center on the fungi Cryptococcus neoformans and Candida auris, which respectively cause cryptococcal meningitis and infections in immune-compromised patients, as well as schistosomiasis, which is caused by a parasitic worm.
“We desperately need drugs for many of these tropical diseases that have just been pretty much ignored,” Wyllie said. “Sitting here in in our labs in Dundee in Scotland, we can make a big difference and potentially help get things to the clinic that can change lives.”