Study seeks new treatments for schistosomiasis

A study led by the Oswaldo Cruz Institute (IOC/Fiocruz) in partnership with British institutions opens the door to the development of new treatments for schistosomiasis. The disease affects 200 million people in 78 countries, including Brazil. It also belongs to the group of neglected diseases, which are associated with poverty and receive low investment in prevention, diagnosis and treatment from the pharmaceutical industry and public policies.

Postdoctoral student Lauro Ribeiro carries out an activity test with the TGR enzyme from the Schistosoma mansoni parasite (photo: Gutemberg Brito)

Using cutting-edge technology, the researchers identified 35 small molecules capable of binding to an important protein of the Schistosoma mansoni parasite, which causes schistosomiasis. With the potential to interfere with the protein's activity, the compounds could be the starting point for developing drugs against S. mansoni.

Leader of the study, Floriano Paes Silva Júnior, head of the Laboratory of Experimental and Computational Biochemistry of Drugs at IOC/Fiocruz, emphasized the importance of developing new drugs against the schistosomiasis worm. "There is currently only one drug available to treat schistosomiasis, which is effective but cannot reach immature forms of the parasite. Additionally, the formulation available is too large for children of school age to swallow, which makes it difficult for them to adhere to the therapy. Finding new molecules active against S. mansoni would provide alternatives for this treatment and prepare us for the possibility of emergence of parasites resistant to the current treatment", said the researcher.

The results of the research were published in the journal Scientific Reports. In addition to IOC/Fiocruz, also took part experts from the University of Oxford, the London School of Hygiene & Tropical Medicine, the Rosalind Franklin Institute and Harwell Science and Innovation Campus in the UK; from the Federal University of Goiás and the University of São Paulo (USP) in Brazil; and from the University of Johannesburg in South Africa.

According to Floriano Paes Silva, the development of drugs from molecular fragments can lead to the creation of compounds with high potency against the schistosomiasis worm (photo: Gutemberg Brito)

Validated target

The research targeted the protein 'thioredoxin glutathione reductase', known as TGR, which has already been validated as a therapeutic target. This is because experiments have shown that its activity is essential for the parasite's survival. "By inhibiting this protein, the parasite dies. That is why attacking this molecule is a strategy for developing a treatment for schistosomiasis", said Floriano.

The study analyzed 768 molecular fragments, which are very small chemical compounds on a sub-nanometer scale. The molecules are part of a library of chemical compounds kept for research purposes. To discover the molecular fragments capable of binding to the TGR protein, the researchers used the high-flow X-ray diffraction crystallography technique, which allows knowing the three-dimensional structure of molecules.

This stage of the tests was carried out at the Diamond Light Source electron accelerator in the UK, a high-tech scientific facility with the automation resources to analyze large libraries of chemical compounds. "Few proteins from parasites causing neglected diseases have been analyzed using this technique, being a first for the TGR protein, from the schistosomiasis worm", Floriano pointed out.

The 35 molecular fragments associated with 16 regions of the protein, called binding sites. Each fragment associated with one or two different binding sites. Only one of these sites had been described in previous research carried out using other methodologies. Like the identification of binders, the mapping of binding sites is considered an important step in the development of new drugs, since in order to inhibit protein activity, compounds need to bind to regions important for their functions.

According to Floriano, two mapped binding sites have the greatest potential for drug development. "We have identified a binding site at the interface of the dimer of this protein, which has never been described before and has a high potential to effectively interfere with the function of the protein and thus kill the parasite", said the researcher. "Another site identified in our work had already been recently described as allowing modulation of the protein's activity, with promising results in an animal model. We have discovered three new binders for each of these sites", he added.

Drug discovery based on molecular fragments is a strategy that seeks to create drugs with high potency and favorable pharmacological properties for treatment, e.g. with the possibility of oral administration and low toxicity. "The results obtained in this work allow us to plan new chemical compounds with greater binding affinity with the target protein and a greater chance of eventually concluding the drug development process", said Floriano.

In the next stage of the research, which is already underway, the scientists are working to synthesize larger molecules from selected molecular fragments. The synthesized compounds will be tested in vitro on the enzyme and the parasite, and subsequently on mice considered as a model for studying schistosomiasis.

Schistosomiasis

According to the Ministry of Health, an estimated 1.5 million people live at risk of contracting schistosomiasis in 18 Brazilian states and the Federal District. From 2009 to 2019, 423 thousand cases of the disease were diagnosed in the endemic areas monitored by the Schistosomiasis Control Program.

Popularly known in Brazil as water belly, xistosis and snail disease, schistosomiasis is linked to precarious conditions or lack of basic sanitation. Contagion occurs in rivers, reservoirs or lakes where sewage is dumped and Biomphalaria snails are present. People infected with S. mansoni release eggs of the parasite in their feces. If the waste is thrown into the water, the eggs hatch, releasing larvae, which infect the snails. Inside these animals, the larvae take the form of cercariae, which are released into the water and can infect humans, penetrating through the skin.

Malaise, fever, pain in the liver and intestines, diarrhea and weakness can all be symptoms of the disease. Weight loss and enlargement of the liver, spleen and stomach occur in severe cases. The disease can also affect the nervous system. Without treatment, schistosomiasis can lead to death. The infection is diagnosed by a stool test. The drug to treat the disease is offered free of charge by the Unified Health System (SUS).