Researchers have identified a new compound that is 100% effective in treating mice and non-human primates infected with Trypanosoma cruzi, the parasite that causes Chagas disease. The compound, known as AN15368, appears to be safe, elicits no significant side effects, and is more effective than existing drugs. Human clinical trials are expected to commence in the next few years.
The work, led by Rick Tarleton, PhD, a professor at the University of Georgia, was published in a Nature Microbiology article entitled “Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.”
T. cruzi is transmitted through the fecal matter of blood-sucking insects known as “kissing bugs,” or Triatoma infestans.Victims can become infected when they unknowingly rub the insect’s feces into their eyes, nose, or an open wound.
The insects thrive in homes with thatched roofs, mud walls, or inadequate protection from the elements, so infections are particularly common in low-income areas of Latin America. Some of the countries with the highest rates of the disease include Bolivia, Venezuela, Argentina, Chile, Mexico, and Brazil.
Nearly all people infected with T. cruzi experience flu-like symptoms such as fever, headaches, and vomiting. But for a subset of patients, the infection can result in severe heart damage that can be both debilitating and life-threatening.
Existing drugs to treat Chagas can pack some serious side effects, and patients must take them for two months.
“Plus they have variable efficacy,” Tarleton pointed out. “I think most physicians in Latin America have to say, ‘We have a drug. It’s going to make you feel bad, and two months later after we finish it, we’re not really going to be able to tell you if it worked or not.’”
Tarleton’s team has been working on a class of boron-containing molecules, the benzoxaboroles, which exhibit potent activity against various protozoans. During the course of their work, they identified a prodrug—a biologically inactive compound that is metabolically activated—that is effective against T. cruzi. This prodrug, called AN15368, is activated by carboxypeptidases in T. cruzi to yield a compound that targets its mRNA processing pathway.
“AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections,” the researchers wrote in their article. “Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact.”
“[It] is the first, extensively validated and safe potential clinical candidate in over 50 yr for the prevention/treatment of Chagas disease,” they continued. Human clinical trials of the compound are expected to begin in the next few years.
“We’ve got something that is as close to effective as it can be in what is as close to a human as it could be, and there aren’t any side effects. That really de-risks it by a lot going into humans,” Tarleton said. “It doesn’t make it fail-safe, but it moves it much further along.”
Over the past several decades, previous treatment candidates went straight from experimental infections in mice to human clinical trials, where they failed to cure the infection. The new drug’s efficacy in non-human primates bodes well for how it will perform in humans.
“I’m very optimistic,” Tarleton said. “I think it has a really strong chance of being a real solution, not just a stand-in for something that works better than the drugs we currently have.”
