Editor's note: Lead compounds for drug discovery do not always need a high-technology genesis, as Antonio Carlos Martins de Camargo, M.D., Ph.D., explains. Dr. Martins de Camargo also describes the education and technology transfer functions of the Center for Applied Toxinology that help develop career opportunities for pharmaceutical research in Brazil. We thank Marcia Triunfol, editor of GrantsNet, for her help with this article.
Poisonous snakes subdue their prey by injecting toxins produced by their venom gland into the victim's blood stream, causing paralysis and death. In the middle of the last century Brazilian scientists Mauricio Rocha e Silva, Sergio Ferreira, and colleagues provided one of the most interesting examples on how science can make use of snake venom.
In 1949 Rocha e Silva discovered that bradykinin, a hypotensive peptide, is produced when the venom of Bothrops jararaca (Bj) is injected into the blood circulation of mammals. This important bioactive peptide is involved in the control of blood pressure and many other physiological and pathological processes. Later, in 1965, his student and collaborator, Sergio Ferreira, discovered that this venom not only generates bradykinin but it also strongly enhances its hypotensive effect through the formation of bradykinin-potentiating peptides (BPPs). The BPPs synergy causes a vascular shock in the snake's prey, usually small mammals.
The pharmacological and molecular features of snake toxins not only led to the discovery of essential endogenous molecules involved in the regulation of blood pressure, but also allowed John Vane (a Nobel laureate) to spotlight the angiotensin I-converting enzyme (ACE) as a target for a drug to treat human hypertension. The work with Bj's toxins led to the development of captopril, the first known active-site directed inhibitor of the ACE, and one of the most successful drugs for the treatment of human hypertension. Captopril was created by the Squibb Institute in 1977. Two years later, the Lasker Award for Clinical Medical Research was given to David Cushman and Miguel Ondetti for their design of ACE inhibitors.
These findings provided the basis for the creation of the Center for Applied Toxinology (CAT) in 2000. The center is a multi-institutional research organization based at the Butantan Institute in São Paulo, Brazil, dedicated to the study of snake toxins and other poisonous organisms. CAT is one of 10 Centers for Research, Innovation and Dissemination ( Centro de Pesquisa, Inovação e Difusão) created by a pioneering program of the Research Support Foundation of the State of São Paulo. The program was established to stimulate research, disseminate knowledge, and foster interaction between science and industry.
During evolution, poisonous snakes became specialized in affecting vital functions of their prey. For instance, venom from Bothrops or Crotalus snakes harm, respectively, the cardiovascular system and the central nervous tissue of their prey. However, snake venoms never limit their action to a single target molecule in order to affect an important physiological function of their prey. Both Bothrops and Crotalus snakes produce a number of toxins (mainly enzymes and peptides) that imbalance the physiological levels of hormones by disturbing the activity of critical enzymes, receptors, or ion channels, thus disarranging the whole cardiovascular or nervous systems of their victims. Moreover, a toxin is frequently associated with a number of highly homologous molecules displaying distinct specificity toward the same target. A good example are the 17 BPP molecules found in Bj venom, each exhibiting distinct specificity toward the active sites of ACE.
The snake venom gland can be seen as the R&D department of a natural pharmaceutical laboratory that helps the survival of the species by mutating and selecting the most appropriate toxins to ensure that sufficient damage is caused to the prey's physiological system.
Due to its high target specificity, snake venom toxins have been used increasingly as pharmacological tools and prototypes for drug development. While pharmaceutical companies spend millions of dollars searching for pharmacological compounds through extensive screening of chemical libraries,1 for millions of years snakes have designed their own blockbuster drugs with the help of natural selection only.
In general, toxins form the main compounds found in venoms, secretions, and other components from a variety of animals, plants, and microbial sources. Toxins can be used for defensive purposes or to damage the cardiovascular and nervous systems, causing blood clotting and fibrinolysis, cell migration, inflammatory processes, paralysis, etc. At CAT, we take a multidisciplinary approach in the investigation of natural toxins that includes isolation and purification, studies of pharmacological actions, toxin structural determination, and structure-function studies and its molecular biology aspects. Several Brazilian institutions are involved with this endeavor that is centralized at the Butantan Institute. CAT also maintains active collaborations with foreign institutions in France, England, the United States, Germany, and Japan.
In Brazil, interaction between academia and industry often leaves much to be desired, and little technological development is found outside Brazilian universities. A country may, if it so decides, build scientific and technical capabilities, but the maturation of such an effort requires time and continuity.
In order to reverse this picture, CAT has established a partnership with a Brazilian pharmaceutical consortium, Coinfar. Within the scope of this partnership, research findings obtained at CAT and evaluated for patent filing have been transferred to drug development in collaboration with Coinfar. A good example of the efforts of this partnership was the development and testing of CAT's first patent-protected drug. The drug's creation was based on a set of antihypertensive peptides found in the venom of the serpent Bothrops jararaca. A team of approximately 30 scientists responsible for different tasks such as conducting animal trials, pharmacokinetic studies, toxicologic tests, among others helped develop the drug. Other toxin-based drugs affecting blood clotting, the cardiovascular system, pain perception, and immune suppression are among those subjected to preclinical trials as a result of the partnership between CAT and Coinfar.
To expedite the patent filing process, CAT created the Agency for Management of Pharmaceutical Innovation (AGIF), dedicated to helping inventors with writing patent proposals and searching for partnerships and investors. AGIF also offers courses on intellectual property.
The educational activity at CAT aims at stimulating highly qualified professionals in the areas related to poisonous animals and their toxins so they can apply this knowledge to developing new pharmaceuticals and/or agrochemical products using biotechnological processes. Additionally, because we believe that scientific literacy is essential for a country's economic development, together with Butantan, CAT has been actively involved with a toxin-related bioliteracy program that includes outreach programs and educational and cultural activities. Butantan's Biological Museum, for instance, exhibits both live and preserved specimens to about half a million visitors per year. The herpetological collection harbors some 60,000 specimens of snakes and serves as a center for studies on distribution, taxonomy, and evolution of snakes.
Together with Butantan, CAT has offered a variety of disciplines to some 2000 students a year. For that, the CAT team relies on its 21 PIs and 19 senior investigators plus international collaborators invited to teach some specialized disciplines. Some disciplines offered at CAT include molecular biology in toxinology, biology of amphibians, laboratory animals, and bacterial, viral, and recombinant vaccines.
The disciplines are grouped according to a field of application such as (i) education in R&D, (ii) accident prevention, (iii) biology of venomous animals, and (iv) systematic and evolution. Many disciplines are taught at different levels, for school children, teenagers, and the general public to undergraduate and graduate students, teachers, and professionals. Additionally, CAT has published specialized books such as the Atlantic Forest Serpents and the Ecosystem of Jureia-Itatins2 (a small remaining part of the Atlantic forest).
Through its partnerships and collaborations, the CAT initiative has opened new opportunities for innovation and for the young scientist interested in drug development. Indeed, when CAT was created 3 years ago, the Brazilian pharmaceutical industry was very skeptical about utilizing academic knowledge and technical-scientific know-how to generate prosperity and innovation. Today, the pharmaceutical companies that constitute the Coinfar have already hired some investigators and have shown interest in hiring an additional number of young Ph.D.s.
At CAT, it is our earnest hope that our combined efforts will launch a new pharmaceutical R&D sector in Brazil.
P. Landers, "Drug industries big push into technology falls short," Wall Street Journal Eastern Edition, 24 February 2004, p. A1. O. A. V. Marques and W. Duleba W (eds.), Holos Editora, Ribeirão Preto, SP, Brazil (2004).
P. Landers, "Drug industries big push into technology falls short," Wall Street Journal Eastern Edition, 24 February 2004, p. A1.
O. A. V. Marques and W. Duleba W (eds.), Holos Editora, Ribeirão Preto, SP, Brazil (2004).