V-ToCs (Venom toxin clustering): A tool for the investigation of sequence and structure similarities in snake venom toxins.

Recently, there has been a major push toward the development of next-generation treatments against snakebite envenoming. However, unlike current antivenoms that rely on animal-derived polyclonal antibodies, most of these novel approaches are reliant on an in-depth understanding of the over 2,000 known snake venom toxins. Indeed, by identifying similarities (i.e., conserved epitopes) across these different toxins, it is possible to design cross-reactive treatments, such as broadly-neutralising antibodies, that target these similarities. Therefore, in this project, we built an automated pipeline that generates sequence and structural distance matrices and homology trees across all available snake venom toxin sequences and structures. To facilitate analysis, we also developed a user-friendly and high-throughput visualisation tool, coined "Venom TOxin CluStering" (V-ToCs). This tool allows researchers to easily investigate sequence and structure patterns in SVTs for a wide array of purposes, such as elucidating toxin evolution, and will also hopefully help guide the discovery and development of increasingly broadly-neutralising antivenoms in the near future.

Phage display assisted discovery of a pH-dependent anti-α-cobratoxin antibody from a natural variable domain library.

Recycling IgG antibodies bind to their target antigen at physiological pH in the blood stream and release them upon endocytosis when pH levels drop, allowing the IgG antibodies to be recycled into circulation via FcRn-mediated cellular pathways, while the antigens undergo lysosomal degradation. This enables recycling antibodies to achieve comparable therapeutic effect at lower doses than their non-recycling counterparts. The development of such antibodies is typically achieved by histidine doping of their variable regions or by performing in vitro antibody selection campaigns utilizing histidine doped libraries. Both are strategies that may introduce sequence liabilities. Here, we present a methodology that employs a naïve antibody phage display library, consisting of natural variable domains, to discover antibodies that bind α-cobratoxin from the venom of Naja kaouthia in a pH-dependent manner. As a result, an antibody was discovered that exhibits a 7-fold higher off-rate at pH 5.5 than pH 7.4 in bio-layer interferometry experiments. Interestingly, no histidine residues were found in its variable domains, and in addition, the antibody showed pH-dependent binding to a histidine-devoid antigen mutant. As such, the results demonstrate that pH-dependent antigen-antibody binding may not always be driven by histidine residues. By employing molecular dynamics simulations, different protonation states of titratable residues were found, which potentially could be responsible for the observed pH-dependent antigen binding properties of the antibody. Finally, given the typically high diversity of naïve antibody libraries, the methodology presented here can likely be applied to discover recycling antibodies against different targets ab initio without the need for histidine doping.

Characterisation of two snake toxin-targeting human monoclonal immunoglobulin G antibodies expressed in tobacco plants.

Current snakebite antivenoms are based on polyclonal animal-derived antibodies, which can neutralize snake venom toxins in envenomed victims, but which are also associated with adverse reactions. Therefore, several efforts within antivenom research aim to explore the utility of recombinant monoclonal antibodies, such as human immunoglobulin G (IgG) antibodies, which are routinely used in the clinic for other indications. In this study, the feasibility of using tobacco plants as bioreactors for expressing full-length human monoclonal IgG antibodies against snake toxins was investigated. We show that the plant-produced antibodies perform similarly to their mammalian cell-expressed equivalents in terms of in vitro antigen binding. Complete neutralization was achieved by both the plant and mammalian cell-produced anti-α-cobratoxin antibody. The feasibility of using plant-based expression systems may potentially make it easier for laboratories in resource-poor settings to work with human monoclonal IgG antibodies.

A single-chain variable fragment selected against a conformational epitope of a recombinantly produced snake toxin using phage display.

Phage display technology is a powerful tool for selecting monoclonal antibodies against a diverse set of antigens. Within toxinology, however, it remains challenging to generate monoclonal antibodies against many animal toxins, as they are difficult to obtain from venom. Recombinant toxins have been proposed as a solution to overcome this challenge, but so far, few have been used as antigens to generate neutralizing antibodies. Here, we describe the recombinant expression of α-cobratoxin in E. coli and its successful application as an antigen in a phage display selection campaign. From this campaign, an scFv (single-chain variable fragment) was isolated with similar binding affinity to a control scFv generated against the native toxin. The selected scFv recognizes a structural epitope, enabling it to inhibit the interaction between the acetylcholine receptor and the native toxin in vitro. This approach represents the first entirely in vitro antibody selection strategy for generating neutralizing monoclonal antibodies against a snake toxin.

Past, Present, and Future of Naturally Occurring Antimicrobials Related to Snake Venoms.

This review focuses on proteins and peptides with antimicrobial activity because these biopolymers can be useful in the fight against infectious diseases and to overcome the critical problem of microbial resistance to antibiotics. In fact, snakes show the highest diversification among reptiles, surviving in various environments; their innate immunity is similar to mammals and the response of their plasma to bacteria and fungi has been explored mainly in ecological studies. Snake venoms are a rich source of components that have a variety of biological functions. Among them are proteins like lectins, metalloproteinases, serine proteinases, L-amino acid oxidases, phospholipases type A2, cysteine-rich secretory proteins, as well as many oligopeptides, such as waprins, cardiotoxins, cathelicidins, and ß-defensins. In vitro, these biomolecules were shown to be active against bacteria, fungi, parasites, and viruses that are pathogenic to humans. Not only cathelicidins, but all other proteins and oligopeptides from snake venom have been proteolyzed to provide short antimicrobial peptides, or for use as templates for developing a variety of short unnatural sequences based on their structures. In addition to organizing and discussing an expressive amount of information, this review also describes new ß-defensin sequences of Sistrurus miliarius that can lead to novel peptide-based antimicrobial agents, using a multidisciplinary approach that includes sequence phylogeny.

Effect of BaltPLA2, a phospholipase A2 from Bothrops alternatus snake venom, on the viability of cells infected with dengue virus.

Dengue fever is considered a major public health problem in tropical and subtropical regions. Our study analyzed the effect of BaltPLA2, a phospholipase A2 from Bothrops alternatus snake venom, on the viability of cells infected with Dengue virus. In presence of BaltPLA2, the viability of infected cells increased significantly in virucidal, post-treatment, and adsorption assays. Although preliminary these results reveal the need for further studies to investigated whether BaltPLA2 has antiviral activity against Dengue virus.

A current perspective on snake venom composition and constituent protein families.

Snake venoms are heterogeneous mixtures of proteins and peptides used for prey subjugation. With modern proteomics there has been a rapid expansion in our knowledge of snake venom composition, resulting in the venom proteomes of 30% of vipers and 17% of elapids being characterised. From the reasonably complete proteomic coverage of front-fanged snake venom composition (179 species-68 species of elapids and 111 species of vipers), the venoms of vipers and elapids contained 42 different protein families, although 18 were only reported in < 5% of snake species. Based on the mean abundance and occurrence of the 42 protein families, they can be classified into 4 dominant, 6 secondary, 14 minor, and 18 rare protein families. The dominant, secondary and minor categories account for 96% on average of a snake's venom composition. The four dominant protein families are: phospholipase A2 (PLA2), snake venom metalloprotease (SVMP), three-finger toxins (3FTx), and snake venom serine protease (SVSP). The six secondary protein families are: L-amino acid oxidase (LAAO), cysteine-rich secretory protein (CRiSP), C-type lectins (CTL), disintegrins (DIS), kunitz peptides (KUN), and natriuretic peptides (NP). Venom variation occurs at all taxonomic levels, including within populations. The reasons for venom variation are complex, as variation is not always associated with geographical variation in diet. The four dominant protein families appear to be the most important toxin families in human envenomation, being responsible for coagulopathy, neurotoxicity, myotoxicity and cytotoxicity. Proteomic techniques can be used to investigate the toxicological profile of a snake venom and hence identify key protein families for antivenom immunorecognition.

Past, present, and future of naturally occurring antimicrobials related to snake venoms

This review focuses on proteins and peptides with antimicrobial activity because these biopolymers can be useful in the fight against infectious diseases and to overcome the critical problem of microbial resistance to antibiotics. In fact, snakes show the highest diversification among reptiles, surviving in various environments; their innate immunity is similar to mammals and the response of their plasma to bacteria and fungi has been explored mainly in ecological studies. Snake venoms are a rich source of components that have a variety of biological functions. Among them are proteins like lectins, metalloproteinases, serine proteinases, L-amino acid oxidases, phospholipases type A2, cysteine-rich secretory proteins, as well as many oligopeptides, such as waprins, cardiotoxins, cathelicidins, and β-defensins. In vitro, these biomolecules were shown to be active against bacteria, fungi, parasites, and viruses that are pathogenic to humans. Not only cathelicidins, but all other proteins and oligopeptides from snake venom have been proteolyzed to provide short antimicrobial peptides, or for use as templates for developing a variety of short unnatural sequences based on their structures. In addition to organizing and discussing an expressive amount of information, this review also describes new β-defensin sequences of Sistrurus miliarius that can lead to novel peptide-based antimicrobial agents, using a multidisciplinary approach that includes sequence phylogeny.

The rise of genomics in snake venom research: recent advances and future perspectives.

Snake venoms represent a danger to human health, but also a gold mine of bioactive proteins that can be harnessed for drug discovery purposes. The evolution of snakes and their venom has been studied for decades, particularly via traditional morphological and basic genetic methods alongside venom proteomics. However, while the field of genomics has matured rapidly over the past 2 decades, owing to the development of next-generation sequencing technologies, snake genomics remains in its infancy. Here, we provide an overview of the state of the art in snake genomics and discuss its potential implications for studying venom evolution and toxinology. On the basis of current knowledge, gene duplication and positive selection are key mechanisms in the neofunctionalization of snake venom proteins. This makes snake venoms important evolutionary drivers that explain the remarkable venom diversification and adaptive variation observed in these reptiles. Gene duplication and neofunctionalization have also generated a large number of repeat sequences in snake genomes that pose a significant challenge to DNA sequencing, resulting in the need for substantial computational resources and longer sequencing read length for high-quality genome assembly. Fortunately, owing to constantly improving sequencing technologies and computational tools, we are now able to explore the molecular mechanisms of snake venom evolution in unprecedented detail. Such novel insights have the potential to affect the design and development of antivenoms and possibly other drugs, as well as provide new fundamental knowledge on snake biology and evolution.

Anti-metaloproteases: produção e caracterização de anticorpos policlonais IgG anti-metaloproteases purificadas do veneno da serpente Bitis arietans

Bitis arietans is a medical importance snake found predominantly in sub-Saharan Africa. The envenomation is characterized by local and systemic reactions, which can lead the victims to death or permanent disabilities. However, the lack of antivenoms makes the treatment worse. Therefore, the present work aimed to identify venom toxins, learn about their properties and develop antitoxins. The F2 fraction obtained from affinity chromatography fractionation of B. arietans venom showed the major proteolytic activity of SVMPs from enzymatic tests. Based on mass spectrometry analysis, 57 different peptides were identified in the F2 fraction. Among the most prevalent peptides are SVMPs. ELISA titration assays performed together with the mouse immunization step (BALB/c) demonstrated the development of anti-F2 fraction antibodies by the animals. The determination of the affinity of antibodies against different Bitis venoms was evaluated, revealing that only the B. arietans venom has peptides recognized by anti-F2 fraction antibodies. In vivo analyzes demonstrated the hemorrhagic capacity of the venom, the effectiveness of the antibodies to inhibit up to 80% of hemorrhage and 0% of the lethality caused by the venom. Taken together, the data indicate: 1) the prevalence of peptides that influence hemostasis and the dissemination of local and systemic effects caused by poisoning; 2) the effectiveness of monospecific antibodies in inhibiting specific activities of the venom; and 3) the isolation of toxins, production and characterization of antibodies is a crucial step in the development of new antivenoms. Therefore, the obtained results help in understanding the mechanism involved in the envenomation and can be useful for the study of new complementary therapies to antivenom in the treatment of accidents by Bitis arietans.

Bitis arietans é uma serpente de importância médica encontrada predominantemente na África Subsaariana. O envenenamento é caracterizado por efeitos locais e sistêmicos, que podem levar a morte ou incapacidades permanentes. No entanto, a carência de antivenenos agravam o tratamento. Portanto, este trabalho teve como objetivo identificar toxinas do veneno, conhecer suas propriedades e desenvolver antitoxinas. A fração F2 obtida do fracionamento por cromatografia de afinidade do veneno de B. arietans, demonstrou a atividade proteolítica majoritária de SVMPs a partir de testes enzimáticos. Com base na análise por espectrometria de massas, foram identificados 57 peptídeos diferentes na fração F2. Entre os peptídeos de maior prevalência estão as SVMPs. Ensaios de titulação por ELISA realizados em conjunto à etapa de imunização de camundongos (BALB/c), demonstraram o desenvolvimento de anticorpos anti-fração F2 pelos animais. A determinação da afinidade dos anticorpos contra diferentes venenos de Bitis foi avaliada, revelando que somente o veneno de B. arietans possui peptídeos reconhecidos pelos anticorpos anti-fração F2. Análises in vivo demonstraram a capacidade hemorrágica do veneno, a eficácia dos anticorpos de inibir em até 80% a hemorragia e em 0% da letalidade causadas pelo veneno. Em conjunto, os dados indicam: 1) a prevalência de peptídeos que atuam influenciando na hemostasia e na disseminação de efeitos locais e sistêmicos causados pelo envenenamento; 2) a eficácia de anticorpos monoespecíficos em inibir atividades específicas do veneno; e 3) o isolamento de toxinas, produção e caracterização de anticorpos é uma etapa crucial no desenvolvimento de novos antivenenos. Desta forma, os resultados obtidos auxiliam na compreensão no mecanismo de envenenamento e podem ser úteis para o estudo de novas terapias complementares ao antiveneno no tratamento dos acidentes por Bitis arietans.

Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins.

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

Bothrops moojeni L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl+ cells.

BACKGROUND: Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl+ leukemic cells and improve the disease treatment. METHODS: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl+ cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro. RESULTS: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl+ cells. CONCLUSION: BmooLAAO-I exerts selective antitumor action mediated by H2O2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.

Bothrops moojeni venom and BmooLAAO-I downmodulate CXCL8/IL-8 and CCL2/MCP-1 production and oxidative burst response, and upregulate CD11b expression in human neutrophils.

Bothrops snake venoms contain biologically active components, including L-amino acid oxidases (LAAO) that induce significant leukocyte accumulation at inflammatory sites characterized by early neutrophil infiltration. As it remains unclear how snake venoms modulate neutrophil activation and chemokine production, here we examined whether Bothrops moojeni crude venom (BmV) and its LAAO (BmooLAAO-I) affect expression of the surface activation markers CD11b and CD66b, production of the chemokines CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8, CXCL9/MIG, and CXCL-10/IP-10, and activation of oxidative burst in human neutrophils. Cell viability, expression of activation markers, and chemokine production were assessed by flow cytometry, while the oxidative burst response was measured by chemiluminescence. BmV at 50 and 75 µg/mL reduced CXCL8/IL-8 (p < 0.001 and p < 0.01, respectively) and CCL2/MCP-1 production (p < 0.05), while BmooLAAO-I at the same concentrations reduced only CCL2/MCP-1 production (p < 0.01). These effects were accompanied by CD11b upregulation (p < 0.05 for 50 and 75 µg/mL BmV; p < 0.01 for 50 and 75 µg/mL BmooLAAO-I) and CD66b downregulation (p < 0.05 for 50 and 75 µg/mL BmV). Both BmV and BmooLAAO-I at concentrations ranging from 0.625 to 5 µg/mL suppressed the oxidative burst of neutrophils stimulated with phorbol 12-myristate 13-acetate, while BmooLAAO-I at 2.5 and 5 µg/mL also suppressed the neutrophil response stimulated with opsonized zymosan. Considering that neutrophils participate in the pathogenesis of autoimmune and inflammatory diseases, the findings reported herein indicate that BmV and BmooLAAO-I are potential immunomodulating agents.

Bothrops moojeni L-amino acid oxidase induces apoptosis and epigenetic modulation on Bcr-Abl+ cells

Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl+ leukemic cells and improve the disease treatment. Methods: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl+ cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro. Results: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl+ cells. Conclusion: BmooLAAO-I exerts selective antitumor action mediated by H2O2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.(AU)

Deep venomics of the Pseudonaja genus reveals inter- and intra-specific variation.

Australian elapid venom remains an under-investigated resource of novel bioactive peptides. In this study, the venom gland transcriptomes and proteomes of the Australian western brown snakes, Pseudonaja aspidorhyncha and Pseudonaja nuchalis, were compared to Pseudonaja textilis. A deep venomics strategy incorporating high throughput 454 pyrosequencing gave a total of 200,911 raw reads for the three venoms. Subsequent annotation identified 5716 transcripts from 20 different toxin families with inter-specific variation between species observed in eight of the less abundant families. Integration of each venom proteome with the corresponding annotated reads identified 65 isoforms from six toxin families; high sequence coverage highlighted subtle differences between sequences and intra and inter-specific variation between species. High quality MS/MS data identified unusual glycoforms with natriuretic peptides from P. aspidorhyncha and P. nuchaliscontaining O-linked trisaccharides with high homology to the glycosylated region of TNPc. Molecular evolutionary assessments indicated the accelerated evolution of all toxin families with the exception of both natriuretic peptides and P. aspidorhyncha PLA2s that were found to be evolutionarily constrained under purifying selection pressures. This study has revealed a wide range of novel peptide sequences from six bioactive peptide families and highlights the subtle differences between toxins in these closely related species. BIOLOGICAL SIGNIFICANCE: Mining Australia's vastly untapped source of toxins from its venomous creatures has been significantly advanced by employing deep venomics methodology. Technological advances in transcriptome analysis using next generation sequencing platforms and proteome analysis by highly sensitive tandem mass spectrometry allowed a more comprehensive interrogation of three underinvestigated brown snake (Pseudonaja) venoms uncovering many novel peptide sequences that are unique to these closely related species. This generic strategy will provide invaluable information when applied to other venomous snakes for a deeper understanding of venom composition, envenomation, venom evolution, as well as identifying research tools and drug leads.

Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat.

CONTEXT: Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). OBJECTIVE: The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. MATERIALS AND METHODS: Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 µg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated. RESULTS: There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration. CONCLUSION: The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.

An alternative method to isolate protease and phospholipase A2 toxins from snake venoms based on partitioning of aqueous two-phase systems

Snake venoms are rich sources of active proteins that have been employed in the diagnosis and treatment of health disorders and antivenom therapy. Developing countries demand fast economical downstream processes for the purification of this biomolecule type without requiring sophisticated equipment. We developed an alternative, simple and easy to scale-up method, able to purify simultaneously protease and phospholipase A2 toxins from Bothrops alternatus venom. It comprises a multiple-step partition procedure with polyethylene-glycol/phosphate aqueous two-phase systems followed by a gel filtration chromatographic step. Two single bands in SDS-polyacrylamide gel electrophoresis and increased proteolytic and phospholipase A2 specific activities evidence the homogeneity of the isolated proteins.

Toxinas de serpientes con alto potencial terapéutico y su uso en la biomedicina / Animal toxins with high therapeutic potential and their use in biomedicine

Los venenos de animales son mezclas complejas de proteínas, péptidos, enzimas y trazas de elementosno proteicos tales como carbohidratos y sales, cuya finalidad es inmovilizar la presa ycomenzar a digerirla; algunos de estos compuestos han sido aislados y caracterizados o descritoscomo toxinas letales, o se les han atribuido acciones potentes sobre proteínas específicas como, porejemplo, las involucradas en la coagulación sanguínea. Debido al descubrimiento en 1971 del péptidoque dio origen al captopril y al entendimiento de los efectos potenciales de las toxinas, se empezó aconsiderar que los venenos de animales son fuentes ricas en compuestos bioactivos, que no soloproporcionan las herramientas necesarias para descifrar los detalles moleculares de diversos procesosfisiológicos, sino que también sirven como fuente de inspiración para diseñar y desarrollaragentes terapéuticos. Este artículo expone la aplicación de nuevas alternativas terapéuticas y demodelos para el diseño de las mismas basados en algunas moléculas aisladas de venenos de serpientescon alto potencial en campos como la biomedicina y la farmacia.

Animal venoms are complex mixtures of proteins, peptides, enzymes and trace elements such ascarbohydrates and salts, which serve to immobilize preys and to begin their digestion. Some ofthese compounds have been isolated and characterized, or described as lethal toxins, while othershave powerful actions on specific proteins, such as those involved in blood coagulation. Due to thediscovery in 1971 of the peptide that gave rise to captopril and to a better understanding of thepotential effects of toxins, animal venoms started to be considered as rich sources of bioactive compounds, which not only provide the necessary toolsto decipher molecular details of various physiologicalprocesses, but also are a source of inspiration to designand develop a range of new therapeutic agents. Thisreview presents the application of new therapeuticoptions or models to design them based on certainmolecules isolated from snake venoms, with highpotential in fields such as biomedicine and pharmacy.