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15 páginas, 5 figuras, 1 tabla. Dispone de información suplementaria de libre acceso en: https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00337, We report a structural and functional proteomics characterization of venoms of the two subspecies (Bothrops bilineatus bilineatus and B. b. smaragdinus) of the South American palm pit viper from the Brazilian state of Rondônia and B. b. smaragdinus from Perú. These poorly known arboreal and mostly nocturnal generalist predators are widely distributed in lowland rainforests throughout the entire Amazon region, where they represent an important cause of snakebites. The three B. bilineatus spp. venom samples exhibit overall conserved proteomic profiles comprising components belonging to 11 venom protein classes, with PIII (34-40% of the total venom proteins) and PI (8-18%) SVMPs and their endogenous tripeptide inhibitors (SVMPi, 8-10%); bradykinin-potentiating-like peptides (BBPs, 10.7-15%); snake venom serine proteinases (SVSP, 5.5-14%); C-type lectin-like proteins (CTL, 3-10%); phospholipases A2 (PLA2, 2.8-7.6%); cysteine-rich secretory proteins (CRISP, 0.9-2.8%); l-amino acid oxidases (LAO, 0.9-5%) representing the major components of their common venom proteomes. Comparative analysis of the venom proteomes of the two geographic variants of B. b. smaragdinus with that of B. b. bilineatus revealed that the two Brazilian taxa share identical molecules between themselves but not with Peruvian B. b. smaragdinus, suggesting hybridization between the geographically close, possibly sympatric, Porto Velho (RO, BR) B. b. smaragdinus and B. b. bilineatus parental populations. However, limited sampling does not allow determining the frequency of this event. The toxin arsenal of the South American palm pit vipers may account for the in vitro recorded collagenolytic, caseinolytic, PLA2, l-amino acid oxidase, thrombin-like and factor X-activating activities, and the clinical features of South American palm pit viper envenomings, i.e., local and progressively ascending pain, shock and loss of consciousness, spontaneous bleeding, and profound coagulopathy. The remarkable cross-reactivity of the Brazilian pentabothropic SAB antivenom toward the heterologous B. b. bilineatus venom suggests that the paraspecific antigenic determinants should have been already present in the venom of the last common ancestor of the Bothrops ″jararaca″ and ″taeniatus″ clades, about 8.5 Mya in the mid-late Miocene epoch of the Cenozoic era. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifiers PXD020043, PXD020026, and PXD020013., This study was partly supported by grant BFU2017-89103-P from the Ministerio de Ciencia, Innovacion y Universidades, ́ Journal of Proteome Research pubs.acs.org/jpr Article https://dx.doi.org/10.1021/acs.jproteome.0c00337 J. Proteome Res. 2020, 19, 3518−3532 3528 Madrid (Spain) to J.J.C. and by Vicerrectori ́ a de Investigacion, ́ Universidad de Costa Rica to B.L. The authors wish to express their gratitude to Conselho Nacional de Desenvolvimento Cienti ́ fico e Tecnologico (CNPq/MCTIC), Coordenac ́ a̧ o de ̃ Aperfeicoamento de Pessoal de Ni ̧ ́ vel Superior (CAPES/ MEC), Fundaca̧ o de Amparo a ̃ ́ Pesquisa do Estado de Saõ Paulo (FAPESP), and Fundaca̧ o Rondo ̃ ̂nia de Amparo ao Desenvolvimento das Aco̧ ̃es Cienti ́ ficas e Tecnologicas de ́ Pesquisa do Estado de Rondônia (FAPERO) for financial support. Authors gratefully thank Dr. Paulo Sergio Bernarde, ́ Universidade Federal do Acre, Campus Floresta, Laboratorió de Herpetologia, Cruzeiro do Sul, Acre, Brazil, for the kind donation of the pictures of B. b. smaragdinus and B. b. bilineatus shown in Figure 1. The venom of Peruvian B. b. smaradignus was used in this study as part of a research agreement signed between the Instituto Nacional de Salud (Peru) and the ́ Universidad Peruana Cayetano Heredia

L-amino acid oxidases are enzymes found in several organisms, including venoms of snakes, where they contribute to the toxicity of ophidian envenomation. Their toxicity is primarily due to enzymatic activity, but other mechanisms have been proposed recently which require further investigation. L-amino acid oxidases exert biological and pharmacological effects, including actions on platelet aggregation and the induction of apoptosis, hemorrhage, and cytotoxicity. These proteins present a high biotechnological potential for the development of antimicrobial, antitumor, and antiprotozoan agents. This review provides an overview of the biochemical properties and pharmacological effects of snake venom L-amino acid oxidases, their structure/activity relationship, and supposed mechanisms of action described so far.

For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP), disintegrins, L-amino acid oxidases (LAAOs), C-type lectins, and phospholipases A2 (PLA2s). Their mechanisms of action include direct toxic action (PLA2s), free radical generation (LAAOs), apoptosis induction (PLA2s, MP, and LAAOs), and antiangiogenesis (disintegrins and lectins). Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development.

Made available in DSpace on 2014-06-24T19:53:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2005Bitstream added on 2014-06-25T11:48:26Z : No. of bitstreams: 1 ISSN1806-8774-2005-7-19.pdf: 34819 bytes, checksum: 9c57c19393d6e0d675158406f7d968ed (MD5) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Faculdade de Medicina de Botucatu UNESP Botucatu São Paulo, Brasil Depto. Parasitologia, Instituto de Biociências de Botucatu - UNESP– Botucatu Faculdade de Ciências Farmacêuticas de Ribeirão Preto/USP Ribeirão Preto Faculdade de Medicina de Botucatu UNESP Botucatu São Paulo, Brasil Depto. Parasitologia, Instituto de Biociências de Botucatu - UNESP– Botucatu