New promising compounds emerge for the treatment of the acute phase of Chagas disease
New promising compounds emerge for the treatment of the acute phase of Chagas disease
New promising compounds emerge for the treatment of the acute phase of Chagas disease
Three new chemical compounds synthesized by scientists from the University of São Paulo (USP) based in the town of São Carlos, Brazil, were successfully tested in mice for the treatment of the acute period of Chagas disease. And preliminary tests carried out during the chronic phase confirm the positive results.
The three substances have in common the ability to inhibit the activity of cross-breeding, an enzyme essential for the survival of the parasite Trypanosoma cruzi, which causes this disease, during all stages of its life cycle.
By testing the compounds in association with benzodidazole, the reference drug, the researchers managed to survive between 60% and 100% of the animals, percentages well above the 10% observed when benzonidazole was applied alone during the acute phase.
"Now we are starting pharmacokinetic tests, which help to understand how substances are metabolized in the body and allow to determine the ideal dose and its administration regime. This information will guide the studies that will lead to progress in preclinical trials, "said Carlos Alberto Montanari, coordinator of the Medicinal Chemistry Group of the Chemistry Institute of São Carlos (IQSC-USP).
The research led by Montanari is carried out with the support of the Foundation for Support of Scientific Research of the State of São Paulo - FAPESP since 2005, within the framework of a program aimed at the planned genesis of drugs. Since 2014, the group has been funded within the Thematic Project entitled "Planning, synthesis and trypanosomicidal activity of reversible covalent inhibitors of the enzyme cruzaína".
In tests conducted with mice in Brazil, one of the substances made 100% of the animals survive in association with benzodidazole, the reference drug. (Image: Mae Melvin-CDC)
The multidisciplinary group is also integrated by the researchers Andrei Leitão (IQSC-USP), Sérgio de Albuquerque (Faculty of Pharmaceutical Sciences of Ribeirão Preto of USP), Antonio Burtoloso (IQSC-USP), Carolina Borsoi Moraes (Federal University of São Paulo ) and Lúcio Freitas Júnior (Institute of Biomedical Sciences of the USP).
"It all started with the discovery of the biomacromolecular target: the cruzipain. This enzyme performs two important functions. First, it helps the parasite recognize, adhere to it and invade the host cell. After that process, it has a second effect: the digestion of proteins in the host cell, "Montanari explained.
Initially, the IQSC-USP group worked on the development of a recombinant version of the cruzipain, which was given the name of cruzaína. To do this, the scientists genetically modified bacteria of the species Escherichia coli to the effect that they happened to express the cruzain in large quantities in the cultures maintained in the laboratory.
Once this was done, it was possible to start the search for chemical compounds capable of inhibiting the activity of the enzyme and perform the first tests of interaction between the molecules.
"We analyzed virtually 100 million chemical substances included in different libraries of molecules from different parts of the world, something that was only possible thanks to the use of artificial intelligence tools such as machine learning [aprendizaje de máquinas], which allow a large amount of data to be analyzed using chemistry methods, in order to find molecular recognition patterns that allow predictions to be made, "Montanari said.
Equipped with computational tools and previously obtained information about the three-dimensional structure of the molecules, the scientists selected the most promising substances to interact with the cruzain and inhibit its biological function through a process called molecular coupling, with which the complex would be predicted. conformed by the enzyme and its inhibitory potential.
After this initial screening, the IQSC-USP group selected and synthesized about 250 small chemical compounds over the course of several years for the performance of the in vitro interaction assays.
"We use the information gathered with the machine learning tools together with the data of the three-dimensional structure of the cruzain obtained by X-ray crystallography. Putting all this together, we can 'memorize' the structure of the molecule that will be synthesized, in such a way that increase the probabilities of success of the inhibition of the enzyme ", explained Montanari.
Initially, the synthesized compounds were tested in vitro against the recombinant enzyme. The objective was to verify if they acted effectively through the interaction mechanism studied by the researchers. Then the most successful candidates were tested directly against the parasite, also in vitro.
Of the 250 compounds initially selected, about six were tested on animals. According to Montanari, only those that were effective at very low concentrations progressed to the in vivo testing stage.
"In practice, we are making the synthesis of molecules following the concept of hypothesis-based planning. In other words: after testing a compound in our in vitro biochemical system, we use the results to plan and perfect the next molecule that will be synthesized. More recently, based on the previous results, we were able to approach the ideal molecular structure and selected 12 chemical substances with potential to work in the preclinical stage with the aim of reaching trials in humans later, "said the researcher.
The first compound tested alone in rodents was not too effective to promote survival, so the scientists decided to continue the trials combining the inhibitors of Cruzipain with benzonidazole, the standard drug in the treatment of Chagas disease.
"Although benzodiazidazole works well during the acute phase, it does not show much efficacy against the parasite during the chronic phase, which can manifest itself many years after the patient is infected with T. cruzi. Also, it is highly toxic and causes many side effects. With combination therapy, we can decrease the doses and adverse effects, "said Montanari.
As explained by the researcher, once the acute phase is over, the parasite can spend years in latency in the human organism without causing symptoms or without being detected in laboratory tests. Only when the complications of the chronic phase arise, such as the widening of the ventricles of the heart (a condition that affects about 30% of patients and that usually leads to heart failure), dilation of the esophagus or widening of the colon (which attacks up to 10% of those infected and can lead to the loss of peristaltic movements and the difficulty of functioning of the sphincters), doctors are able to establish the diagnosis.
"During this stage of the disease, when it is already possible to detect the parasite again in the body, we intend to test our possible drugs. Today there is no effective therapeutic option for the chronic phase. That's why we devise this combination therapy, "said the researcher.
The tests were carried out with mice infected with the Y strain of the parasite, considered one of the most virulent found in Brazil. According to Montanari, the compounds synthesized at USP revealed a strong synergistic effect when combined with benzonidazole.
"We apply a new concept, widely used in the United States by the FDA [la Food and Drug Administration, la agencia de control sanitario de ese país], which consists of administering a subtherapeutic dose with the hope of mitigating the adverse effects of the substances in isolation. Apparently we succeeded, because no mice died and we did not observe any adverse effects, "said the scientist.
With three of the six compounds tested in animals, the researchers were able to establish the ideal dose ratio of both substances (benzonidazole and the inhibitor of cruzipain). All belong to the chemical type of mimetic peptides, that is, they exhibit physicochemical properties similar to those of peptides, but their chemical structure is not peptidic. Therefore, they are not digested by enzymes in the stomach and can be administered orally, and generally have greater chemical stability.
"They are showing good performance in the treatment of the chronic phase in rodents. We are now awaiting the conclusion of pharmacokinetic trials to refine the administration regimen and dose. Later we intend to associate with the pharmaceutical industry, within the framework of a public-private partnership. After the preclinical stages, the process becomes extremely expensive and it is not feasible to carry it forward only in the university, "said the researcher. (Source: AGENCIA FAPESP / DICYT)
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