Finding the “perfect molecule” to inhibit the development of diseases is one of the objectives of the partnerships of the Unicamp Center for Medicinal Chemistry
By improving the search for target molecules, the Unicamp Medicinal Chemistry Center (CQMED) developed strategies to accelerate the discovery of chemical probes and make it possible to explore potential therapeutic targets, through a partnership program, called Target Enabling Packages (TEP).
The result of these studies can be the obtaining of the 3D structure of the target molecule, the identification of chemical probes and the characterization of biochemical activity. With all this information, an informed decision can be made about the feasibility of moving forward with the development of chemical probes.
CQMED's TEP program encompasses a set of reagents, methodologies and molecular tools to study and validate new therapeutic targets. The program operates under an open science system, in which all information is available to any research group or company.
The TEP program is a pioneer in Brazil and is the result of CQMED's participation in the international consortium Structural Genomics Consortium (SGC), which develops TEPs for little-known proteins that have a genetic correlation with human diseases. Since the program began in 2015, the SGC has developed TEPs for 29 proteins, including those related to cancer, inflammation, metabolic diseases, neurological disorders and malaria. CQMED implemented the TEPs program in Brazil in 2017, however, in addition to proteins linked to human diseases, the Brazilian initiative also covers proteins of agricultural importance.
To develop TEPs, researchers have access to the infrastructure, reagents and expertise of researchers at the Center for Medicinal Chemistry. "Collaborating researchers can produce the protein of interest in bacteria or insect cells so that they can be purified, subsequently crystallized and thus have their three-dimensional structure revealed", explains Katlin Massirer, researcher at the Center for Molecular Biology and Genetic Engineering (CBMEG ) and coordinator of CQMED. Furthermore, the Center develops biochemical and biophysical assays to characterize the protein and find chemical molecules in its vast library of compounds that are capable of blocking the activity of target proteins. With this, researchers are able to understand, for example, how the organism behaves in the absence of this substance, therefore contributing to understanding its biological function.
The pprocess involved
It takes, on average, 15 years to develop a medicine from the original idea to the pharmacy shelf and costs around US$2,5 billion. This process results from long stages of research and development, starting with the identification of a possible therapeutic target - that is, finding the key molecule that, when “turned off”, stops the development of a disease - and going through the discovery, optimization and characterization of compounds that act on the target and, at the same time, are not toxic to the human body. These studies are essential to assess the initial safety of the molecule and constitute the so-called discovery phase.
Finding the "perfect molecule" to be the basis of a therapeutic strategy involves large volumes of testing, followed by adjustments, and new tests and repetitions, and more adjustments and more tests and as much as necessary, until a consistent result is achieved for proceed to the next phase. The molecule will then have its effectiveness evaluated in treating the disease through pre-clinical studies (tests on animals) and clinical studies (tests on healthy and sick humans).
This is an extremely refined drug development strategy that, in addition to focusing on high efficiency in combating the disease, is also concerned with avoiding inconvenient side effects that medications generally present. This happens, for example, when taking certain medicines for nausea and having sleepiness as a side effect, or in more delicate situations, the adverse effects of chemotherapy such as fatigue, hair loss, bruising and bleeding. This often occurs because the medicine, although it works to combat the disease, also ends up interacting with other proteins in the body, generating side effects. Therefore, a good active ingredient must be specific and powerful enough to interrupt only the chains of reactions linked exclusively to the functioning of the disease. And this process is not simple.
One of the strategies is to find so-called chemical probes, small molecules synthetic substances that interact with the target molecule. It is a time-consuming and expensive path.
It is in the search to find these target proteins and design chemical probes that the Center for Medicinal Chemistry (CQMED) works, whether for cancer, leishmaniasis, infections, among others.
From neglected diseases to witches' broom
The doctoral students from Universidade Estadual Paulista - Unesp de Araraquara, Suelen Fernandes Silva and Angélica H Klippel, are at CQMED to unveil the structure of an enzyme (protein) essential for most living beings, including parasites as agents that cause malaria, chagas and leishmaniasis. “There are several studies showing that this enzyme can be a therapeutic target for cancer and inflammatory diseases, as it acts on cell proliferation,” says Klippel. “However, there are still few studies for neglected diseases such as malaria and chagas,” adds Silva. The challenge of the São Carlos duo's research is to develop a specific inhibitor that acts only on the parasite and that does not affect human proteins. To do this, they have the infrastructure and the entire team of crystallographers and medicinal chemists to find differences between parasite and human proteins and be able to design a specific inhibitor that does not affect the human protein. “Our goal is to develop drugs for neglected diseases” explains Klippel.
Although the TEPs approach prioritizes studying molecules associated with human diseases, it can also be applied to the investigation of other organisms. The researcher at the Campinas Agronomic Institute, IAC, Jorge Maurício Costa Mondego, is a collaborator who participates in the TEP program to study a cocoa tree protein. The abundance of this protein increases significantly when infected by the fungus that causes the disease known as witches' broom. “We want to understand how plants use these receptors to combat pathogen infection,” explains Mondego. At CQMED Mondego produced and purified part of the protein he is studying and confirmed that it has a phosphorylative, that is, kinase. The researcher believes that it is capable of causing a cascade of signals that culminates in the plant's response to infection by the parasite. Now the IAC researcher is looking for molecules capable of inhibiting the action of the protein and, therefore, understanding what happens to the cocoa tree exposed to witches' broom in the absence of this protein. "These studies will help us understand how increased expression of this protein can be related to pathogen attack and, perhaps, produce a cocoa tree resistant to witches' broom", adds Mondego.
By following the guidelines of the SGC international consortium, all TEPs are necessarily open access, that is, all information is available on the SGC websites. SGC e CQMED, any research group and/or company can access the results and develop them into new research, new articles or new medicines. “We adopted a model for developing chemical molecules that is open, that is, without patents. The knowledge produced is available to universities and the pharmaceutical industry in order to accelerate the development of new medicines”, explains CQMED scientific director Rafael Couñago.
The TEPs program is financed by the São Paulo State Research Support Foundation (Fapesp) and the Ministry of Science and Technology, Communication and Information (MCTIC), which promoted CQMED as one of the Institutes of Science and Technology (INCT).
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