RESUMEN

The process of discovering and developing new drugs costs billions of dollars and can take more than ten years. The search for new drugs begins with some form of screening of libraries of chemical compounds that often contain a variety of natural products. Venoms contain toxins with extremely specific functions, therefore being a secretion of great potential in the search for new bioactive compounds. In the era of Next Generation Sequencing and shotgun proteomics, a large number of data of toxins and venom protein sequences from venomous animals have been generated. Thus, there is great interest in applying computational methodologies to facilitate parts of the screening of peptide and proteins for biological activity. To assist in the characterization and search for new toxins and antiviral peptides in arachnid venoms, two computational methods were developed: ArachnoFamTox and EnAVPClass. ArachnoFamTox performs the prediction and classification of arachnid toxins and venom proteins with an approach that uses evolutionary conservation information with Position Specific Scoring Matrices and Hidden Markov Models and is the most specific predictor of toxins among the existing methods and one of the few that classify toxins in families. EnAVPClass predicts antiviral peptides and classifies them according to their mechanism of action. The method uses an approach based on Supervised Machine Learning with Random Forest and Support Vector Machines models and Deep Learning with Long Short Term Memory neural networks. As an example of application of the developed tools, transcriptomes of seven tick species were processed and assembled de novo and the ArachnoFamTox and EnAVPClass tools were used for the prediction and classification of toxins and prediction of Antivirals. A total of 2.069 toxins and venom proteins classified in 13 different families were identified and 47.160 peptides were generated, of which 3.559 antiviral peptides (7.54%) were predicted. Of these, 1.765 were identified as Antivirals that act on virus membranes, 755 on viral replication and 64 on viral assembly. The results show the importance of ticks as promising organisms in the discovery of new antiviral compounds based on their saliva and venom proteins. The tools developed in this work will be available as packages open source in https://github.com/yutakajr after publication and will help in the process of discovering new drugs in silico, classifying families of toxins in arachnids and in the development of new tools.

O processo de descoberta e desenvolvimento de novas drogas tem um custo de bilhões de dólares e pode durar décadas. A procura por novas drogas começa com alguma forma de screening de bibliotecas de compostos químicos que geralmente contém uma variedade de produtos naturais. Os venenos contém toxinas com funções extremamente específicas sendo uma secreção de grande potencial na procura por novos compostos bioativos. Na era do Sequenciamento de Nova Geração e proteômica shotgun, é gerado um grande número de dados de sequências de toxinas e proteínas de veneno de animais venenosos. Assim há um grande interesse em aplicar metodologias computacionais para agilizar partes do processo de screening de sequências de peptídeos e proteínas que possam ter atividade biológica e potencial para serem desenvolvidos novos medicamentos. Para auxiliar na caracterização e busca por novas toxinas e peptídeos antivirais em venenos de aracnídeos, foram desenvolvidos dois métodos computacionais: o ArachnoFamTox e o EnAVPClass. O ArachnoFamTox realiza a predição e classificação de toxinas e proteínas de veneno de aracnídeos com uma abordagem que utiliza informações da conservação evolutiva com Position Specific Scoring Matrices e Hidden Markov Models e é o preditor de toxinas com maior especificidade dentre os métodos existentes e um dos únicos a classificar em famílias de toxinas. O EnAVPClass faz a predição de peptídeos antivirais e classifica-os de acordo com seu mecanismo de ação. O método utiliza uma abordagem baseada em Aprendizagem de Máquina Clássico com modelos de Random Forest e Support Vector Machines e Aprendizagem Profunda com redes neurais do tipo Long Short Term Memory. Como exemplo de aplicação das ferramentas desenvolvidas, foram processados e montados de novo transcriptomas de sete espécies de carrapatos e utilizadas as ferramentas ArachnoFamTox e EnAVPClass para a predição e classificação de toxinas e predição de Antivirais. Foram identificadas 2.069 toxinas e proteínas de veneno classificadas em 13 diferentes famílias e gerados 47.160 peptídeos dos quais foram preditos 3.559 peptídeos antivirais (7.54%). Desses, 1.765 foram identificados como Antivirais que agem nas membranas dos vírus, 755 na replicação viral e 64 na montagem viral. Os resultados evidenciam a importância dos carrapatos como organismos promissores na descoberta de novos compostos antivirais baseados em suas proteínas de saliva e veneno. As ferramentas desenvolvidas neste trabalho ficarão disponíveis como pacotes open source https://github.com/yutakajr após publicação e auxiliarão no processo de descoberta de novas drogas in silico, classificação de famílias de toxinas em aracnídeos e no desenvolvimento de novas ferramentas.

RESUMEN

Arachnida is the largest class among the arthropods, constituting over 60,000 described species (spiders, mites, ticks, scorpions, palpigrades, pseudoscorpions, solpugids and harvestmen). Many accidents are caused by arachnids, especially spiders and scorpions, while some diseases can be transmitted by mites and ticks. These animals are widely dispersed in urban centers due to the large availability of shelter and food, increasing the incidence of accidents. Several protein and non-protein compounds present in the venom and saliva of these animals are responsible for symptoms observed in envenoming, exhibiting neurotoxic, dermonecrotic and hemorrhagic activities. The phylogenomic analysis from the complementary DNA of single-copy nuclear protein-coding genes shows that these animals share some common protein families known as neurotoxins, defensins, hyaluronidase, antimicrobial peptides, phospholipases and proteinases. This indicates that the venoms from these animals may present components with functional and structural similarities. Therefore, we described in this review the main components present in spider and scorpion venom as well as in tick saliva, since they have similar components. These three arachnids are responsible for many accidents of medical relevance in Brazil. Additionally, this study shows potential biotechnological applications of some components with important biological activities, which may motivate the conducting of further research studies on their action mechanisms.

RESUMEN

Arachnida is the largest class among the arthropods, constituting over 60,000 described species (spiders, mites, ticks, scorpions, palpigrades, pseudoscorpions, solpugids and harvestmen). Many accidents are caused by arachnids, especially spiders and scorpions, while some diseases can be transmitted by mites and ticks. These animals are widely dispersed in urban centers due to the large availability of shelter and food, increasing the incidence of accidents. Several protein and non-protein compounds present in the venom and saliva of these animals are responsible for symptoms observed in envenoming, exhibiting neurotoxic, dermonecrotic and hemorrhagic activities. The phylogenomic analysis from the complementary DNA of single-copy nuclear protein-coding genes shows that these animals share some common protein families known as neurotoxins, defensins, hyaluronidase, antimicrobial peptides, phospholipases and proteinases. This indicates that the venoms from these animals may present components with functional and structural similarities. Therefore, we described in this review the main components present in spider and scorpion venom as well as in tick saliva, since they have similar components. These three arachnids are responsible for many accidents of medical relevance in Brazil. Additionally, this study shows potential biotechnological applications of some components with important biological activities, which may motivate the conducting of further research studies on their action mechanisms.(AU)

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RESUMEN

Arachnida is the largest class among the arthropods, constituting over 60,000 described species (spiders, mites, ticks, scorpions, palpigrades, pseudoscorpions, solpugids and harvestmen). Many accidents are caused by arachnids, especially spiders and scorpions, while some diseases can be transmitted by mites and ticks. These animals are widely dispersed in urban centers due to the large availability of shelter and food, increasing the incidence of accidents. Several protein and non-protein compounds present in the venom and saliva of these animals are responsible for symptoms observed in envenoming, exhibiting neurotoxic, dermonecrotic and hemorrhagic activities. The phylogenomic analysis from the complementary DNA of single-copy nuclear protein-coding genes shows that these animals share some common protein families known as neurotoxins, defensins, hyaluronidase, antimicrobial peptides, phospholipases and proteinases. This indicates that the venoms from these animals may present components with functional and structural similarities. Therefore, we described in this review the main components present in spider and scorpion venom as well as in tick saliva, since they have similar components. These three arachnids are responsible for many accidents of medical relevance in Brazil. Additionally, this study shows potential biotechnological applications of some components with important biological activities, which may motivate the conducting of further research studies on their action mechanisms.

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