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International Year of Chemistry

Pharmacological Battles

Cutting-edge science seeks solutions for neglected tropical diseases

PEDRO HAMDANScience needs to advance a great deal as regards the treatment of diseases that affect 20% of the population inhabiting the poorest regions on the earth. Diseases such as malaria and leishmaniasis are referred to as neglected tropical diseases, as most of the underdeveloped countries lie in tropical regions. But the fact is that these diseases are associated with a lack of economic resources, poor sanitation, and inadequate health care; these diseases exist in tropical regions where there is a lot of poverty. Fighting these diseases goes beyond science; it is also necessary to fight the irremediable injustices of our times, said chemist Carlos Montanari, from the University of São Paulo (USP) in São Carlos, at the opening of the sixth meeting of the cycle of conferences organized by FAPESP and by the Brazilian Chemistry Society within the scope of the International Year of Chemistry. “Mitigating the status of neglected tropical diseases is an intervention to promote social change,” he added.

The pursuit of this objective, which goes beyond science, as attested to in a number of conferences on chemistry, also entails crossing the boundaries of traditional disciplines. Indeed, the lectures held on September 14 brought together an electrical engineer who had become a physicist, an industrial chemist with a doctorate degree in organic chemistry and currently a professor at a physics institute, and a chemist specialized in cell and molecular biology. These leaders in the field of pharmaceutical drug development, who met in FAPESPS’s auditorium were, respectively, Glaucius Oliva and Adriano Andricopulo, of the Physics Institute of USP in São Carlos, and Celia Garcia, of the Biological Sciences Institute (IB) of USP.

Global Threat
In line with his current position as president of the National Scientific and Technological Development Council (CNPq), Glaucius Oliva was attuned not only to research, but also to the training of young students – represented in the audience by students from the Barueri Technical Institute and from the Atenas Educational Institute, in Arujá. “You are our biggest asset,” said the physicist, whose tie imitated a blackboard with formulas and calculations written in white chalk.

Having successfully lectured to an eclectic audience, Oliva described the impact caused by neglected tropical diseases. “These diseases can cause blindness, and disfiguration. They stigmatize and potentially kill people,” he warned, pointing out that there are currently approximately one billion people in the world who are infected by one or more of these diseases. Another two billion people live in hazardous areas. These diseases represent a threat to one half of the world’s population.

Oliva said that most of the medical drugs still being prescribed nowadays had been developed prior to 1950, when the European colonizers in Africa had to deal with these diseases to ensure their own survival. The result of the end of the colonial period is an ancient and extremely limited group of pharmacological drugs that has never really been updated. In the last few decades, the enormous financial investments made by the pharmaceutical industry for the development of new drugs did not have a significant impact in terms of mitigating the suffering of the affected populations.

In spite of very few practical developments, the biochemical understanding of those diseases has advanced tremendously since the 1950’s. This existing knowledge has guided the group led by Oliva at the Center of Structural Molecular Biotechnology (CBME), one of the Centers of Research, Innovation and Diffusion (Cepid) funded by FAPESP. Oliva said that the way substances and cell receptors fit in can be compared to the diversity of electric power outlets, which is something that people travelling abroad worry about when they think of how they will be able to plug in the hair dryers they are carrying in their suitcases. “Brazilian electric power outlets have recently undergone changes and have become resistant to electrical appliances,” he joked, referring to the recent changes in the country’s electrical power standards. As a result, older electrical appliances have to be plugged into adapters. This concept of fitting in is the basis of the modern development of pharmaceutical drugs, which differs considerably from the trial and error approach that had guided historical advances in medicine, such as the discovery of penicillin.

“It is very important to establish the structure of the receptors,” he explained. By resorting to techniques that examine and build molecule models, physicists can contribute towards the study of diseases. It is possible to locate the targets on the basis of a basic knowledge of organisms and the proteins that cause the disease and find molecules that block the receptors.

SAMUEL IAVELBERGAdriano Andricopulo, Célia Garcia and Glaucius OlivaSAMUEL IAVELBERG

Chagas Disease is an example. This is an endemic disease in Latin America; it causes 43 thousand deaths a year among 18 million infected patients. There is no efficacious treatment for the disease. One approach is to find molecules in Brazil’s biodiversity that could generate a new pharmaceutical component. By resorting to models of the structure of target receptors in the membrane of the parasite or in the host cells, researchers nowadays can accurately define the necessary properties in a compound that deactivates a given receptor. This is like a jigsaw puzzle, where one looks for a part that has a rounded bulge or an inward angle in the midst of hundreds of tiny parts. In chemistry, the properties sought for in molecules are the capacity to attract or repel water, or the tendency to bind with specific elements. “We can see how a plant molecule fits into an active site of the Trypanosoma cruzi to fight Chagas Disease,” he explained.

Adriano Andricopulo, also linked to the CBME, agreed. “The development of a new drug to fight Chagas Disease is very urgent.” In his opinion, a possible target is cruzaine, a major protein in the parasite’s entire cycle life. Various inhibitors of this protein have already been described in literature, but so far none have resulted in a medical drug that could be widely prescribed for the disease. The same holds true for other diseases, such as tuberculosis and malaria. The research team from São Carlos is looking for target proteins to then find new compounds that can block such proteins. An automated large scale biological triage study was conducted with the collaboration of Pfizer, in view of the fact that the pharmaceutical industry has more and better resources than those of university laboratories. In this case, the objective was to find anti-malaria treatments by means of experimental essays to identify compounds able to block thioredoxin reductase, a protein found in the Plasmodium falciparum, the parasite that causes one of the forms of malaria. “All strategies are possible, as long as modern methods are resorted to,” he pointed out.

Iconic test tubes have little space in this modern arsenal. Most of the search for active principles is now conducted through virtual models of proteins and promising compounds. By using three-dimensional computer illustrations, researchers can conduct a virtual triage and evaluate whether the target molecules can alter the protein or block essential changes that can prevent its functioning. This resembles a jigsaw puzzle, much like the old-fashioned Tetris.

But the work does not stop at this point. It is useless to find a perfect fit if the compound is unable to reach the target protein. Some medications can be administered orally, for example, while others only work if they are injected directly into the blood stream. Properties such as absorption and bioavailability, referred to as pharmacokinetics, have to be taken into account when medical drugs are being developed. “The therapeutical effect involves not only the active principle but also the combination of pharmacokinetic properties,” said Andricopulo. With this in mind, and with the objective of building upon the work of several other research teams, the researchers from São Carlos are working on a data base that will be available for free. The data base will contain the pharmacokinetic and physical-chemical properties of hundreds of compounds.

The biology of malaria
Another approach transcends molecular analysis by taking the biological context into consideration also. By using this approach, Celia Garcia described how malaria could be fought through a combination of biochemistry and the molecular and cell biology of plasmodium, the malaria-causing parasite. After being injected into the blood stream by the anopheles mosquito, the tiny parasite lodges in the liver during one phase before invading the erythrocytes, the red blood cells.

In their search to discover how the plasmodium reproduces itself, the group discovered an active exchange of information between the parasite and the host. The group found that this exchange of information indicates the existence of very specific receptors found in the cells’ membranes, as if though there were an intercom between the plasmodium and the red blood cells. Celia’s research team has pioneered the unveiling of this kind of signaling.

In the course of all these years, the researchers from IB have increased their knowledge of the factors that result in a successful invasion. It was a challenge for the group to search for the code used for this communication: the researchers had no leads for the function of 60% of the Plasmodium falciparum’s genome, sequenced in 2002. With the help of bio infotech, the researchers found four genes that indicate the so-called serpentine receptors of the parasite’s membrane. These receptors act as antennae for communication with the host. “The cell of the plasmodium needs to capture what is outside,” Celia explained. The researchers have recently discovered which molecules bind with two of these receptors. This was a huge step forward for pharmaceutical research, as it was an innovative way of trying to sabotage the communication that is crucial for the invading parasite.

But it is not enough to enter the cells. “The relationship between the host and the parasite is essential for regulating the pace of the disease,” says Celia. This relationship is mediated by the ATP (the substance that acts as the cell’s energy source) and by melatonin (the hormone whose peak release activity occurs at midnight). “The plasmodium perceives the environment inside the erythrocytes and synchronizes the life cycle.” Her team has already identified and is studying two plasmodium proteins that bind with melatonin. Based on this discovery, the chemist from IB has been testing synthetic molecules that block the action of the melatonin on the parasite, which may improve the action of anti-malaria drugs.

The search for new pharmacological pathways is important because existing medications are not efficient enough. Atovaquone, for example, a medication prescribed to prevent malaria, is expensive and needs to be taken with fatty foods. “In collaboration with Vitor Ferreira, of Fluminense Federal University, we have discovered a less expensive and more efficient compound,” said Celia, in line with the idea of innovative ways to develop medical drugs.

The three lectures opened a window on how biology, chemistry and physics interact to understand and fight diseases. The lectures also unveiled a complexity that answers the reasons why the development of cures is so slow.