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Structural tools to further understanding structural-functional mechanisms of toxins and development specific inhibitors

Abstract

Neglected tropical diseases (NTD) are defined by World Health Organization (WHO) as "a diverse group of communicable diseases that prevail in tropical and subtropical conditions in 149 countries - affect more than one billion people and cost developing economies billions of dollars every year. Populations living in poverty, without adequate sanitation and in close contact with infectious vectors, domestic animals and livestock are those worst affected". Several diseases, such as Dengue, Chagas disease, Leishmaniasis and Rabies affect strongly Brazil and Latin America populations. In addition, snake envenomation is also considered a NTD by WHO for some decades, but in the World Health Assembly occurred on May 2018 was approved an important resolution with a strong mandate for global action sponsored by governments of more than 31 countries (particularly from Latin America, including Brazil) and a strategic plan to reduce snakebite deaths, morbidity and disability is being prepared. 2-3 millions of cases of envenomings occurs each year, resulting in more than 100,000 deaths and around three times as many amputations and other permanent disabilities each year. Thus, in this proposal we intent to use a broad combination of Biophysical, Biochemical and Bioinformatics tools applied to particular biological systems in order to advance in the understanding of these systems and for the identification, characterization and development of substances with biotechnological and pharmacological usefulness. This proposal is focused in snake venom toxins (from Bothrops and Crotalus genus) aiming to further understand the biological mechanisms of particular toxins and also to perform the selection/synthesis of new molecules from the modification of inhibitors with biotechnological/therapeutic potential using biophysical and bioinformatics tools. It is important to highlight that about 90% of reported snakebites are caused by bothropic snakes, whose envenomation is characterized by intense local myonecrosis inefficiently neutralized by antivenom. Thus, it is very important to develop drugs to control of symptoms that cannot be prevented or reverted by serum therapy administration and as aid for the treatment of the underlying pathological process. In addition, as some of these toxins displays several pharmacological activities such as, immunomodulatory, anti-inflammatory, analgesic activities and anti-tumor activities, the detailed structural-functional information could be important for the design of new pharmacological agents. These research topics are related with the main subject studies by our research group in the last 20 years, leading to more than hundred scientific papers published and important contributions for science and for training human resources. This project is aligned with more than a dozen of projects successfully coordinated by us and supported by FAPESP and CNPq since 1997 and dozens of collaborations in Brazil and with researcher in different countries. On the other hand, this proposal is also innovative, because the approaches proposed here was not used to date to solve the specific biological problems presented here and may lead to development of new substances with biotechnological impact. (AU)

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