Cyanotriazoles show antiparasitic promise

Chagas disease, caused by the parasite Trypanosoma cruzi, infects 6–7 million people, mostly in Latin America, according to the World Health Organization. Current treatments for the disease have severe side effects and are not always effective against chronic infections.

Now, researchers from Novartis and their academic collaborators found that cyanotriazole compounds block a crucial enzyme for Trypanosoma parasites’ DNA replication, quickly eliminating infections in mice (Science 2023 DOI: 10.1126/science.adh0614).

“This is really exciting for us because we have the potential to change the next generation of treatment,” says Srinivasa Rao, the Novartis researcher who led the project.

Rao’s team screened 2 million compounds from Novartis’ library in search of molecules that inhibited T. cruzi and its relatives, including T. brucei, which causes sleeping sickness. They identified cyanotriazoles as potent parasite killers. Medicinal chemists iterated on the structure to come up with a candidate compound, CT3, which has good solubility, bioavailability, and the ability to cross the blood-brain barrier.

It took only 5 days for CT3 to eliminate T. cruzi from infected mice, and the infection did not relapse, even in immunosuppressed mice with chronic infections. As little as one dose was enough to clear mice of a T. brucei infection.

The researchers also thoroughly investigated how cyanotriazoles defeat parasites. They determined that they target an enzyme called topoisomerase II, which has a vital role in DNA replication. Cryo-electron microscopy confirmed that the cyanotriazole group covalently binds to a cysteine residue that only the parasite versions of the enzyme have.

Rick Tarleton, a trypanosomiasis researcher at the University of Georgia who was not involved in the study, says the target characterization was “beautiful work.” He adds that cyanotriazoles look promising, though fully eliminating T. cruzi infection is “a hard bar to reach” and he’d like to see more sensitive assays to show that they work as quickly and thoroughly as claimed.

The researchers’ next steps are to assess a selection of cyanotriazoles’ safety in further animal studies before advancing a candidate into a clinical trial. “I’ve been working on trying to get new drugs for trypanosomiasis for my entire career,” says Mike Barrett of the University of Glasgow, who worked on the mouse experiments. “This is just really exciting that we seem to at least have a view as to where we might be going.”