Chagas: drug against leukemia can fight parasite – 07/12/2023 – Science

Article published in Journal of Biological Chemistry describes a molecule capable of inhibiting in vitro the proliferation of the parasite that causes Chagas disease.

The study was conducted by researchers from Unifesp (Federal University of São Paulo) and CQMED-Unicamp (Center for Medicinal Chemistry at the State University of Campinas), a National Institute of Science and Technology (INCT) supported by FAPESP.

According to data released by the Ministry of Health, the difficulty of diagnosis and treatment has made Chagas disease one of the four leading causes of death from infectious and parasitic diseases in the country, with an average of 4,000 cases per year over the last ten years.

The disease is caused by the protozoan Trypanosoma cruzi and transmitted by insects (triatomines) popularly known as kissing bugs or weevils. If not treated, it can cause irreversible and lethal damage to the heart and other vital organs.

So far, there are only two drugs available: nifurtimox and benznidazole. According to the Drugs for Neglected Diseases Initiative (DNDi), about 20% of patients discontinue treatment because of side effects, which include gastric intolerance, skin rashes and neuromuscular problems.

“The treatment options are still very toxic, that is, to attack the parasite the medicine ends up affecting other processes in our body, generating undesirable side effects”, explains Katlin Massirer, coordinator of CQMED and author of the study. One of the alternatives is to find drugs that reach only the focus of the disease.

“The identification of target proteins in the parasite that are relevant for the development of drugs is still a challenge in general. When considering parasitic protozoa, this is particularly difficult, since they have different enzymatic and metabolic pathways”, he explains. Masirer.

The first step in this search is to validate proteins that can be a good target for the development of molecules that are the basis for generating new drugs. In the case of Chagas disease, ideally it should be a target capable of specifically interrupting some important process for parasite proliferation, without affecting other processes in the human body.

Groups from Unifesp and Unicamp have been studying the enzyme called TcK2. “It is a new potential target, given its central role in the intracellular phase of the life cycle of the Trypanosomathat is, if we inhibit its functions, the parasite does not multiply at the same speed”, explains Sergio Schenkman, professor at Unifesp and author of the study. T. cruzi It basically alternates between a free-living phase and an obligatory intracellular phase, of infection in the host, when multiplication is more accelerated.

For this target, the researchers tested 379 inhibitor molecules and only two had the potential to inhibit TcK2. Among them, the molecule called dasatinib had a better performance in inhibiting the enzyme, causing the slowdown of the proliferation of the parasite in cultured cells, in the laboratory.

“To ensure that the molecule was acting on TcK2, we tested dasatinib in Trypanosoma genetically modified, without TcK2, and the inhibitor molecule had no effect”, explains Schenkman. “Dasatinib blocks the proliferation of the parasite only in cells that express TcK2, validating that this enzyme is the target of the compound”, adds Massirer.

Dasatinib is already a drug used in the treatment of acute and chronic myeloid leukemias. “The therapy is effective because of the high sensitivity to dasatinib of a protein that is altered in myeloid leukemia. However, in current dosing regimens, dasatinib does not reach a sufficient concentration to inhibit T. cruzi proliferation. Therefore, they are needed improvements”, explains Schenkman. Furthermore, the drug has a high cost, reaching R$ 15,000 per month, an amount inaccessible to a large part of the population, especially those exposed to the risk of the disease.

Once this target has been validated in the parasite and using dasatinib as a starting point, an inhibitor molecule may be found. For this, the scientists intend to advance in the understanding of how the connection between the inhibitor and the enzyme occurs and then study ways to make the molecule more potent and specific. The next step will be to test it on laboratory animals.

One possibility, according to Schenkman, is that these new compounds are useful for developing a drug acting in combination with other existing ones. “The combined use of new drugs could speed up treatment, reduce doses, side effects and treatment abandonment rates, as TcK2 acts on the parasite”, adds the researcher.

The study also received funding from FAPESP through a thematic project. And it had the collaboration of researchers from Unesp (São Paulo State University), in Araraquara, Drug Discovery and Evaluation Unit, University of Dundee (United Kingdom), Charles University (Czech Republic) and UFMG (Federal University of Minas Gerais).

The article Identification of inhibitors for the transmembrane Trypanosoma cruzi eIF2α kinase relevant for parasite proliferation can be read here.

* With information from CQMED, a National Institute of Science and Technology supported by FAPESP.