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New weapon against arterial hypertension

CAT/Cepid, in partnership with the pharmaceutical industry, registers a patent for anti-hypertension medicine

The Center of Applied Toxicology (CAT) of the Butantan Institute, registered with the National Institute of Industrial Property (INPI) the patent for the active ingredient of a molecular prototype that will be used in the production of a drug with anti-hypertension properties. Baptized with the generic name of Evasin (endogenous vasopeptidase inhibitor), the new medicine has the potential to compete with Captopril, an anti-hypertension drug produced by Squibb, that guarantees to this multinational pharmaceutical company an annual income estimated in US$ 5 billion throughout the world. The patent will also be registered in the United States, Japan and the European Union (EU). The expectation is that Evasin will be available to hypertensive patients in the next few years. “Now, we have to carry out the pre-clinical and clinical tests.” announced Antonio Martins de Camargo, the Director of CAT.

In the development of Evasin, the center will have as its partner the National Pharmaceutical Consortium (Coinfar), formed by the laboratories Biolab-Sanus, Biosintética and União Química. “The private companies have the necessary flexibility and agility to push forward a project such as this since the public institutions don’t have the experience of the market.” says Dr. Camargo.

The CAT is one of the ten Research Centers, Innovation and Diffusion (Cepids) certified by FAPESP and the partnership with the pharmaceutical industry for the development of the new medicine responds to one of the main requirements of the program which is that of putting together the academic activities of research with the market forces. Before the registration with the INPI, FAPESP evaluated the patent of Evasin through the of the Support Program of Intellectual Ownership (PAPI/Nuplitec). “Our aides understood that this drug has tremendous market potential.” says Dr. José Fernando Perez, Scientific Director of the Foundation.”  Three laboratories joining us shows that the evaluation is correct.”

FAPESP has been supporting the research activities of CAT since September of last year, when the Cepid Program was launched. “The investigations had begun before this date. Nevertheless, more that 90% of the investments in the research into Evasin, both in material, post-doctorate and post-graduate scholarships and equipment, has been financed by FAPESP through assistance grants.” points Dr. Camargo.

The ownership of the patent will belong to FAPESP and the consortium partnership (Coinfar), in accordance with the terms of the internal regulations of the Foundation. The sales revenues of the product will be shared among the inventors, the Butantan Institute, the private partners and FAPESP. It is up to the consortium of laboratories topick up the expenses of the patent in Brazil and abroad, the administration of CAT/Cepid and the investments in the infra-structure of the research laboratories of the Center, which will be equipped with FAPESP funding. It is also planned that the private partners must finance the clinical tests necessary for the development of the drug. FAPESP has committed itself to supporting the activities of the Center with R$ 3 million per year for a period of up to eleven years. The Butantan Institute, like the other institutions that make the group of ten Cepids, is responsible for the payroll of the researchers and the support personnel, and it will provide the installations, equipment and other material in the development of the research.

Dr. Camargo believes that the drug may hit the market within two years, since everything indicates that the molecular prototype, the basis of Evasin, seems to be part of the endogenous system of the arterial pressure of human beings. This means that Evasin itself could be used as a medicine. “The disadvantage is that, as we are speaking of a peptide, it cannot be administered orally because of the risk of being destroyed within the stomach, as is the case of insulin or of growth hormones. Therefore, it should be provided to patients in an injection form or in a spray”. These are among the methods that are being developed by modern pharmaceutical techniques for the use of peptides as medicines, forecast Dr. Camargo.

Nor are they discarding the possibility of the clinical tests indicating another alternative for the oral administration of the anti-hypertensive, which could be obtained by molecular and biological molecular modeling. “In this case, we will probably have as a partner the National Laboratory of Synchronized Light (Laboratório Nacional de Luz Síncontron) in Campinas.” say Dr. Camargo. “If we adopt this procedure, the medicine will only be available in the market in five or six years.” he advises.

Selective action
A great advantage of Evasin, whatever the form it is administered to the patients, is that it is a natural product with selective activity and is not immunogenic, and has a prolonged effect. Indeed, these characteristics were the starting point of the research that led to the discovery of the new drug. “We tried to find this anti-hypertensive in nature, looking at substances capable of inhibiting the action of enzymes which cover the blood vessels (vasopeptidases) and whose malfunction can lead to arterial hypertension, such as the enzyme converter of angiotensin, known as ACE, and the neutral endopeptidase, known as EP 24.11. These enzymes are fundamental for maintaining our arterial pressure at normal values, controlling the blood concentration of angiotensin II and bradykinin, avoiding arterial hypertension.” explains Dr. Carmargo.

Since these two substances are vital for the organism, with the ability to produce a cardio circulatory shock or arterial hypertension which can lead to death, the CAT team bet that nature, along the millions of years of evolution, would also have selected endogenous inhibitors of these enzymes capable of maintaining them at normal levels, in kind of defense action of living organisms.

The cardiovascular physiopathology, over the last few decades, has found positive responses to problems of arterial pressure, inflammatory processes, pain mechanisms, allergic processes and bronchial asthma, among so many others, in research with animal poisons. It is already known that, throughout a process of mutations and natural selectivity, the snakes developed “weapons”, starting from endogenous substances, capable of acting upon enzymes disorganizing the cardiocirculatory system of their victims. Attempting to explain how the poison of the jararaca snake kills or paralyses its victims, in 1948, Gastão Rosenfeld, of the Butantan Institute, took to the laboratory of Maurício Rocha and Silva a sample of the venom of the Bothrops jararaca with the objective of studying its effects on dogs.

The researchers incubated the venom with dog plasma and from this reaction a substance was formed that strongly contracted the intestines of the guinea pigs and dramatically lowered the blood pressure. This substance was not histamine, but a polypeptide that was named bradykinin. Rocha and Silva discovered that the jararaca snake, on injecting the venom into its victim when feeding or defending itself, injects toxins that disorganize the system of coagulation and liberates the bradykinin, leading to hypotension, to the unbalancing of various systems of the cells and the liquids of the blood, thus paralyzing or endangering the life of its prisoner. Therefore, the toxins of the serpents put in evidence the cellular mechanisms and molecular demonstrations in the anaphylactic and allergic reactions, among other reactive effects of the organism.

Millions of dollars
Later on in the 60’s, Sérgio Ferreira, ex-student of Rocha and Silva, confirmed that the hypotension provoked by the liberation of bradykinin into the blood of the victim was capacitated by the action of minute toxins found in large quantities in the venom of the jararaca snake. These minute toxins, denominated bradykinin potentiator peptide or BPPs, were isolated by Ferreira and collaborators and taken to the Imperial College of London, permitting that the English scientist John Vane (Nobel Prize winner) arrive at the molecular prototype that would give origin to the billionaire captropil of Squibb, the first of a series of anti-hypertension drugs used by millions of people. From that time on, the pharmaceutical industry throughout the world, began to invest millions of dollars in the development of anti-hypertension drugs. “The value of this discovery remained almost exclusively with the English and the Americans.” relates Dr. Camargo. “Everyone knows that hypertension is an illness that attacks a large part of humanity, above all the elderly, but few know that the anti-hypertension medicine most used in the world comes from research which began in Brazil fifty years ago.

The team of researchers of CAT retook the path followed by Rocha and Silva and Ferreira. They identified, via molecular biology, a predecessor protein of the BPPs in the gland where the venom of the Bothrops jararaca is formed. “We found seven BPPs and a molecule of a natriuretic hormone on the same protein, as if it was a rosary of anti-hypertension molecules, capable of causing a cardiovascular shock in the victim who has been bitten by this snake” outlines Dr. Camargo. Recently the team verified, by molecular biology, that these BPPs are not just toxins, but make part of the endogenous system for the regulation of arterial pressure. The efficiency of these peptides was tested in rats. The research advanced, and in partnership with Dr. Vincent Dive, of CEA in France, the team of CAT concluded that the action of these synthetic peptides (BPPs), besides inhibiting the enzymes which cover the blood vessels important in causing the hypertension (ACE and EP 24.11), have a selectivity for one of the “heads” of the enzyme converter of angiotensin (ACE).

Immunological defense
This enzyme, ACE, present on the walls of the blood vessels, is fundamental for the steadying our arterial pressure. It possesses two active “heads”, identified as C and N. The two “heads” can generate the angiotensin II and consequently produce hypertension. The situation becomes worse since both the ACE and the EP 24.11 can inactivate the bradykinin, a natural hypotensive substance. The two “heads”, nonetheless, are not equal. The C “head” is more specific in forming the angiotensin II and inactive to bradykinin. The N “head” does the same thing, but less efficiently. However, it carries out another important function for the organism, that inactivating a hormone recently discovered, the AcSDKP, that regulates the proliferation of cells of the blood responsible for the immunological defense. Neither Captopril nor its more modern derivatives are capable of distinguishing between the C and N “heads”, inhibiting the two heads equally.

Its prolonged use can lead to alterations in the blood cells. To hit the target, or that is to say, the C “head” with a selective, safe and more efficient anti-hypertensive has been one of the great challenges of the multinational pharmaceutical industry. Evasin has these characteristics. It is a selective medicine for the C “head” of ACE, and as well, inactive to EP 24.11. The patent which is registered also grants to the owners the rights to the endogenous BPPs and their derivatives, denominated Evasins, that possess greater selectivity for the C “head” of the enzyme converter of angiotensin (ACE).

Recreation of nature
Besides Dr. Camargo, other researchers take part of the CAT group of this project. They are the post doctorates Miriam Hayahiand Fernanda Portaro, and doing her master’s is Danielle Yanzer along with the science undergraduate Alessandra Murbach, all with scholarships from FAPESP among others. “We have found in nature the substance that possesses the properties of the new anti-hypertensives that the multinationals pharmaceutical companies have been looking for.” explains Dr. Carmargo. “The pathway adopted by the CAT team was distinct from that used by the North American company Millennium, that attempted to get to the modern anti-hypertensives using genomic information and chemical combination. “We are using, for this same finality, not the recreation of nature by man, which can be highly frustrating, but we are trying to discover the pathways that nature itself uses.” states Dr. Camargo.

For the Scientific Director of FAPESP, the perspectives that open up with the registering of the patent of Evasin “are an auspicious beginning” for the Cepids. “It shows that this model of partnerships is a strong stimulus to interaction with the private sector. The project CAT/Cepid will have special success in the relations between the academic sector and the pharmaceutical industry, traditionally shy about this type of relation.” said Dr. Perez.