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From natural toxins to novel drugs
Abstracts/Toxicon 38 (2000) 487 595
497
Toxinology is an expanding field of knowledge which integrates many basic and applied scientific disciplines, as well as various technological areas. The development of Toxinology in Latin America has played an important role in several fields, particularly in Biology, Pharmacology, Biochemistry and Experimental Pathology, as well as in the Clinical Sciences. However, the progress in other fields of Toxinology has not been so impressive. Several factors may explain this phenomenon: (1) There is a strong tradition in some areas which determines the emphasis followed by some groups and institutions. (2) There is a tendency towards dispersion of efforts, with little integration of disciplines and groups. (3) Some areas of scientific work demand expensive equipment which, in many cases, is out of reach for individual institutions and groups. (4) With few notable exceptions, there is little integration between basic and clinical sciences in Latin America, and between the scientific community and the industrial sector. It as necessary to develop a cooperative and integrated regional approach to develop Toxinology into a strong scientific field in our countries. This effort must include: (1) The development of centers of excellence in the fields of Molecular Biology and Protein Biochemistry, including facilities to carry out sequence and crystallographic work. These facilities should support collaborative projects with countries in the region. (2) The fields of Pharmacology and Experimental Pathology must be strengthened, to investigate activities of venoms and toxins and to work in prospection studies aimed at the identification of potential lead compounds from Latin America biodiversity. (3) The establishment of links between research centers and pharmaceutical and biotechnological industries in the region. This relationship must promote the development of expertise in the performance of clinical trials. Concomitantly, this will provide a renewed source of funds for basic and applied research in the area. (4) Finally, there is a strong need to support technological development in the area of antivenom production, in order to assure that all the countries in the region will have access, in the near future, to sufficient amounts of effective antivenoms for the treatment of poisonings. This goal implies a strong relationship between health authorities, research centers, pharmaceutical industries and clinicians.
Front natural toxins to novel drugs. Mario Sergio Palma (Laboratory Structural Biology and Zoochemistry/CEIS/CEVAP Institute of Biosciences of Rio ClaroUNESP, Rio Claro, SP, Brazil). Venoms and toxins of natural origin have long fascinated men due to their interesting pharmacological and neurochemical properties. Historically, initial interest in molecular and mechanistic studies of venoms and natural toxins, was to develop the means to prevent or reverse their toxic actions. Because of the lethality, some of these actions are of clinical interests and have been studied for many years. Up to early of nineties the use of classical protocols of purification and structure determination required the manipulation of large amount of biological material, permitting to deal only with the major compounds, especially proteins. However, progress in toxinology paralleled progress in methodology.
498
Abstracts/Toxicon 38 (2000) 487-595
Thus, the advances in techniques for the analysis of three dimensional structures, microanalytical spectroscopy, peptide chemistry and computational chemistry permitted the detection and structure elucidation of several new compounds. These improvements boosted the studies to establish the relationship between the molecular structures and biological activities, whose in collaboration with computer aided drug-design contributed to make several toxins "lead-compounds" in drug discovery. As consequence many natural toxins became useful academically tools to elucidate physiological mechanisms. Beyond to this, the progress in toxinology combined with some new methodological approaches formed the basis for the present upsurging of neurochemistry: recombinant gene technology (especially in collaboration with patch-clamp electrophysiology) and molecular immunology, originating the modern neurotoxinology. Following the same general tendency described above, neurotoxins acting selectively in the nerves became widely used as tools by the modern neurosciences, mainly for the purposes of: mapping neuronal pathways, elucidation of function and animal models of disease. The keen interest by the natural toxins attracted the attention of pharmaceutical and agrochemical companies, to use them as starting point in the design of new drugs, for therapeutical use and/or as agents for insect-pest control. To understand this as a tendency of the present research in toxinology, it would be interesting to verify the current number and types of applications based on venom toxins registered in the United States Patent and Trademark Office (USPTO): 154 patents for ~nake venom toxins-based applications. 28 patents for spider venom toxin-based applications. 16 patents for scorpion venom toxin-based applications and 4 patents for wasp venom toxin-based applications. The applications include new medicines (drugs for neurodegenerative diseases, cardiac diseases, immunosupressants), diagnostic reagents, selective bioinsecticides and scientific tools. The most of applications for snakes, scorpions and wasps venom toxins are directed to scientific tools, while for spider venoms are concentrated in selective bioinsecticides. Among the 137 patent applications based on neurotoxins presently registered in USPTO, 29 were developed from natural sources (15 from spiders and scorpions, 4 from snakes, 6 from microorganisms, 1 from plant and 3 from marine organisms). Thus, it became apparent the potential of venoms and natural toxins as molecular models for the rational development of novel commercial drugs for different practical purposes. Presently substantial fractions of the medicines currently in use were derived, directly or indirectly, from natural toxins produced by venomous animals, plants or microorganisms. The present tendency is showing that the contemporaneous toxinology got an important status in the frontiers of science. Lectures Crotoxin inhibitor from Crotalus durissus terrificus serum is specific of the Viperidae phospholipase A2 neurotoxins. G. Faure a, J. Perales b, C. Bon a (aUnit6 des Venins, Institut Pasteur, 25 rue du Dr Roux, 75724, Paris, France; bDepartamento de Fisiologia e Farmacodinfimica, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil).
497
Toxinology is an expanding field of knowledge which integrates many basic and applied scientific disciplines, as well as various technological areas. The development of Toxinology in Latin America has played an important role in several fields, particularly in Biology, Pharmacology, Biochemistry and Experimental Pathology, as well as in the Clinical Sciences. However, the progress in other fields of Toxinology has not been so impressive. Several factors may explain this phenomenon: (1) There is a strong tradition in some areas which determines the emphasis followed by some groups and institutions. (2) There is a tendency towards dispersion of efforts, with little integration of disciplines and groups. (3) Some areas of scientific work demand expensive equipment which, in many cases, is out of reach for individual institutions and groups. (4) With few notable exceptions, there is little integration between basic and clinical sciences in Latin America, and between the scientific community and the industrial sector. It as necessary to develop a cooperative and integrated regional approach to develop Toxinology into a strong scientific field in our countries. This effort must include: (1) The development of centers of excellence in the fields of Molecular Biology and Protein Biochemistry, including facilities to carry out sequence and crystallographic work. These facilities should support collaborative projects with countries in the region. (2) The fields of Pharmacology and Experimental Pathology must be strengthened, to investigate activities of venoms and toxins and to work in prospection studies aimed at the identification of potential lead compounds from Latin America biodiversity. (3) The establishment of links between research centers and pharmaceutical and biotechnological industries in the region. This relationship must promote the development of expertise in the performance of clinical trials. Concomitantly, this will provide a renewed source of funds for basic and applied research in the area. (4) Finally, there is a strong need to support technological development in the area of antivenom production, in order to assure that all the countries in the region will have access, in the near future, to sufficient amounts of effective antivenoms for the treatment of poisonings. This goal implies a strong relationship between health authorities, research centers, pharmaceutical industries and clinicians.
Front natural toxins to novel drugs. Mario Sergio Palma (Laboratory Structural Biology and Zoochemistry/CEIS/CEVAP Institute of Biosciences of Rio ClaroUNESP, Rio Claro, SP, Brazil). Venoms and toxins of natural origin have long fascinated men due to their interesting pharmacological and neurochemical properties. Historically, initial interest in molecular and mechanistic studies of venoms and natural toxins, was to develop the means to prevent or reverse their toxic actions. Because of the lethality, some of these actions are of clinical interests and have been studied for many years. Up to early of nineties the use of classical protocols of purification and structure determination required the manipulation of large amount of biological material, permitting to deal only with the major compounds, especially proteins. However, progress in toxinology paralleled progress in methodology.
498
Abstracts/Toxicon 38 (2000) 487-595
Thus, the advances in techniques for the analysis of three dimensional structures, microanalytical spectroscopy, peptide chemistry and computational chemistry permitted the detection and structure elucidation of several new compounds. These improvements boosted the studies to establish the relationship between the molecular structures and biological activities, whose in collaboration with computer aided drug-design contributed to make several toxins "lead-compounds" in drug discovery. As consequence many natural toxins became useful academically tools to elucidate physiological mechanisms. Beyond to this, the progress in toxinology combined with some new methodological approaches formed the basis for the present upsurging of neurochemistry: recombinant gene technology (especially in collaboration with patch-clamp electrophysiology) and molecular immunology, originating the modern neurotoxinology. Following the same general tendency described above, neurotoxins acting selectively in the nerves became widely used as tools by the modern neurosciences, mainly for the purposes of: mapping neuronal pathways, elucidation of function and animal models of disease. The keen interest by the natural toxins attracted the attention of pharmaceutical and agrochemical companies, to use them as starting point in the design of new drugs, for therapeutical use and/or as agents for insect-pest control. To understand this as a tendency of the present research in toxinology, it would be interesting to verify the current number and types of applications based on venom toxins registered in the United States Patent and Trademark Office (USPTO): 154 patents for ~nake venom toxins-based applications. 28 patents for spider venom toxin-based applications. 16 patents for scorpion venom toxin-based applications and 4 patents for wasp venom toxin-based applications. The applications include new medicines (drugs for neurodegenerative diseases, cardiac diseases, immunosupressants), diagnostic reagents, selective bioinsecticides and scientific tools. The most of applications for snakes, scorpions and wasps venom toxins are directed to scientific tools, while for spider venoms are concentrated in selective bioinsecticides. Among the 137 patent applications based on neurotoxins presently registered in USPTO, 29 were developed from natural sources (15 from spiders and scorpions, 4 from snakes, 6 from microorganisms, 1 from plant and 3 from marine organisms). Thus, it became apparent the potential of venoms and natural toxins as molecular models for the rational development of novel commercial drugs for different practical purposes. Presently substantial fractions of the medicines currently in use were derived, directly or indirectly, from natural toxins produced by venomous animals, plants or microorganisms. The present tendency is showing that the contemporaneous toxinology got an important status in the frontiers of science. Lectures Crotoxin inhibitor from Crotalus durissus terrificus serum is specific of the Viperidae phospholipase A2 neurotoxins. G. Faure a, J. Perales b, C. Bon a (aUnit6 des Venins, Institut Pasteur, 25 rue du Dr Roux, 75724, Paris, France; bDepartamento de Fisiologia e Farmacodinfimica, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil).