For most of us in the developed world, parasites are a distant menace and not given much thought. But for millions in poorer nations, parasites and the deadly infections they cause pose a constant threat to health and survival. Yet many of the infectious diseases caused by parasites are neglected: Few treatments are available for those afflicted.
Now, working with preclinical models, a team led by researchers at the Genomics Institute of the Novartis Research Foundation (GNF) has identified a potential way to tackle not one, but three neglected diseases. In Nature this week, the scientists show that a single compound can cripple the parasites responsible for African sleeping sickness, leishmaniasis and Chagas disease, which cause symptoms in close to 1 million people per year.
“We found that these parasites harbor a common weakness,” says corresponding author Frantisek Supek, a senior investigator at GNF. “We hope to exploit this weakness to discover and develop a single class of drugs for all three diseases.”
On the surface, the three diseases—responsible for 50,000 deaths annually—seem quite distinct. As its name suggests, African sleeping sickness is found in Africa and affects the central nervous system, causing behavioral changes, confusion and sleep disruptions. Leishmaniasis is more widespread. In the cutaneous form of the disease, the infection leads to skin and mouth sores in infected individuals across Asia, Africa and Latin America. Even more dangerous—and often life-threatening—is the visceral form of leishmaniasis, found mainly in India.
Chagas infections occur primarily in Latin America, but also, through travel and immigration, in the United States and Europe. These infections—which often go unnoticed at first—can eventually cause intestinal complications and heart failure.
Even the insect that carries each disease is different: tse-tse flies for sleeping sickness, sand flies for leishmaniasis, and triatomine “kissing bugs” for Chagas disease.
But the infections do have one thing in common: All three are caused by parasites that belong to the same class of single-celled organisms—the kinetoplastids. This shared ancestry is what prompted the team to search for a shared weakness and exploit it to the patient’s advantage.
Searching for a shared weakness
When the researchers started the project, they didn’t have a specific drug target in mind. So they turned to an unbiased approach for leads.
The team tested more than three million compounds in high-throughput screens, applying each compound to cultures of Trypanosoma cruzi, Leishmania donovani and Trypanosoma brucei, the microbial parasites that cause Chagas, leishmaniasis, and sleeping sickness, respectively. They then tested the compounds that were successful against the parasites in a separate screen on mammalian cells. The goal was to identify compounds that would be effective against the parasites but not toxic to humans.
One compound, GNF5343, jumped out as a promising starting point. A chemistry team led by Advait Nagle synthesized more than 1,000 analogues of the starting compound to make it more potent and more like a drug candidate.
In parallel, a group began to search for its target. Postdoctoral researcher Shilpi Khare exposed generations of the T. cruzi parasite to increasing concentrations of the compound until the microbes developed resistance. The team then performed whole genome sequencing on the compound-resistant strains, comparing their genomes with those of the original strain to see where mutations had developed.
A surprising target
Among the many mutations they saw were several clustered in a gene that codes for the proteasome, a cellular complex that plays an essential role in degrading and recycling damaged and unwanted proteins. The convergence of these mutations suggested that the proteasome must be the target of GNF5343, a hypothesis they confirmed in subsequent experiments.
“The discovery of this shared target was something of a surprise,” says Supek. “The proteasome has not generally been considered a target in parasitic diseases because parasite and human proteasomes are actually quite similar. Somehow our molecule singles out the region that is uniquely different from the human proteasome and selectively kills the parasites while having no effect on human cells.”
When the team tested the optimized version of GNF5343 in mice with the three kinetoplastid diseases, the animals were cured of their infection.
“What is remarkable about this compound is that, in addition to curing all three of these kinetoplastid diseases in mouse models, it appears to spare human cells,” Nagle says. “This therapeutic target holds promise for treating patients with African sleeping sickness, leishmaniasis and Chagas disease.”
This work was supported in part by grants from the Wellcome Trust and NIH.
Main image: African sleeping sickness, leishmaniasis and Chagas disease are all caused by parasites that belong to the same class of single-celled organisms: the kinetoplastids. The kinetoplastid parasite shown here causes leishmaniasis. SEM micrograph by Zephris/WikimediaCommons