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Studies of pieces of one heart replaced by another during a transplant found one of the causes of the progression of heart failure and to develop a molecule to treat this disease .
The research directed by Júlio César Batista Ferreira was launched in 2009
The work was carried out by researchers from the Universities of São Paulo (USP) and Stanford, USA, and was published January 18 at the University of São Paulo. Nature Communications scientific journal.
As the name suggests, heart failure is characterized by the heart's poor ability to pump blood to the rest of the body and may be caused by a heart attack, hypertension or other health problems. organ valve. This is the last phase of several cardiovascular diseases, which kills the most in the world. According to the World Health Organization (WHO), an estimated 17.7 million people died worldwide because of them in 2015.
During the research, which began in 2009, scientists, led by Brazilian Júlio César Batista Ferreira of the USP Institute of Biomedical Sciences (ICB), discovered a mechanism that advances heart failure. It is the interaction between two proteins, Beta 2 kinase (Beta2PKC) and Mitofusin 1 (Mfn1), inside the mitochondria, the organelle of the cell responsible for the energy production for the operation of the human body, including the heart.
According to Ferreira, when both proteins interact, Beta2PKC disables Mfn1, which interferes with mitochondrial function and prevents it from producing energy. As a result, it decreases the contraction and expansion capacity of the heart muscle cells and, consequently, the pumping of the blood.
"This interaction between the two proteins, until then unknown in the progression of heart failure, was one of the main discoveries of our work," says the researcher.
After deactivating Mfn1, Beta2PKC begins to accumulate inside the mitochondrion. In previous work, the team led by Ferreira had already succeeded in inhibiting this second protein and this process of accumulation. As a result, the functioning of the heart with insufficiency has improved.
"The problem is that this solution has also prevented Beta2PKC from baduming other proper functions, beneficial for the functioning of the heart muscle," Ferreira said.
It is at this point that the researchers have come up with the new molecule, which acts selectively, preventing only Beta2PKC from disabling Mfn1 in the mitochondria. To create it, the researchers tested recombinant proteins (produced by genetic engineering, that is to say artificially from cloned genes), cells and pieces of insufficient human heart tissue and animals.
Thus, the molecule was named SAMbA, acronym for selective antagonist of mitofusin 1 and Beta2-PKC combination – or selective antagonist of the combination of mitofusin 1 and Beta2PKC . This name was not created by chance. It is inspired by the most popular musical rhythm of the country.
"As it was an important work done in Brazil, I thought nothing was more right than leaving a Brazilian mark in this story," Ferreira explains.
"We place great value on what comes from the outside and little on what is here, and SAMbA serves to maintain the heart's rhythm."
Ferreira explains that SAMbA was synthesized in the laboratory from peptides (protein parts) acting on the heart cells and designed to block the interaction between Beta2PKC and Mfn1. First of all, in vitro tests were performed. In total, six molecules were created and tested. All inhibited the interaction between the two proteins, but only SAMbA selectively did so, preventing Beta2PKC from disabling Mfn1.
The next step was to test the new molecule, still in vitro, directly on human heart cells.
"The results showed that he was able to prevent the progression of heart failure and to improve the ability of cardiac cells to contract and expand, which is necessary for pump the blood to the rest of the body, "said Ferreira.
They were divided into two groups and, for six weeks, one received a treatment with the new molecule and the other, which served as a control, a placebo (no effect substance).
In those who were actually treated, the disease was blocked and there was also an improvement in cardiac function.
"Current drugs prevent the progression of heart failure, but never make it regress," says Ferreira.
Our work shows that by preventing the interaction between Beta2PKC and Mfn1 proteins, SAMBA not only reduces progression, but also makes the disease less severe.
Ferreira attributes the good results of the new molecule to a unique characteristic of it. "Current drugs work outside the diseased cell, especially on the membrane," he says.
"They do not act in the cell itself.Samsa, on its own account, acts within the mitochondrial mechanism, and corrects the problem, it produces an effect of inside. "
Despite the good results, the molecule developed by the Ferreira group will take some time to give birth to a new drug for heart failure.
"What we have for the moment, it's a prototype," he says.
"We must now move to the development phase." To turn SAMbA into a drug, it takes another eight years of research, possibly in partnership with the pharmaceutical industry, to test it on people with the disease. interaction with other medications that the patient takes because it must have an additional effect on them. You can not take the medicines they take to test you. "
Whatever the case may be, the SAMbA patent has already been filed in the United States. Despite this, it will be made available to other researchers and institutions to test and continue their development.
"We are already discussing with some pharmaceutical companies that have expressed interest in advancing studies on the molecule we have created and making it a new drug," Ferreira said.
"But as it's a new treatment for humans, it takes time."
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