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Bioprospection of low molecular weight anticancer molecules from Bothrops genus snake venom

Grant number: 22/04804-6
Support Opportunities:BIOTA-FAPESP Program - Regular Research Grants
Duration: November 01, 2022 - October 31, 2024
Field of knowledge:Health Sciences - Pharmacy - Toxicological Analysis
Principal Investigator:Suely Vilela
Grantee:Suely Vilela
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers:Norival Alves Santos Filho

Abstract

Snake venoms are complex mixtures of biological active compounds, among them, still little explored, the low molecular weight compounds, as the peptides, organic compounds and lipids. These molecules have diversified pharmacology activity and has been waking up a crescent scientific interesting about their anticancer potential. Although there are several peptides related with Bothrops genus snake, these studies were conducted only about the bradykinin potentiating peptides and the C-natriuretic, about their hypotensive activity (LAMEU et. al., 2013). The peptide composition of these venoms, although, represents 4.72% of disintegrins and 1.23% of other classes, as the cathelicidins, with known antitumoral activity, but they have never been actually isolated (MUNAWAR et. al., 2011). This way, the present study aims isolate molecules until 10 kDa, from Bothrops genus snake venoms, with antitumoral action, in approach that considers direct or biological pathways pharmacological effects, that are included in the most actual aspects of comprehension of tumorigenesis and its therapy. The bioprospection of these compounds will use different tumoral cell lineages (HepG2; DU-145; A549; MDA-MB-231; THP-1 and HL-60) for the identification of cytotoxic activities, and non-cytotoxic in vitro tumorigenesis inhibition mechanisms, such as the modulation of cellular migration and proliferation.The crude venom will be ultrafiltrate in specific membranes, isolating the compounds with low molecular weight and this pool will be fractionated through molecular exclusion chromatography. The bioactive molecules will be identified in these fractions by in vitro biological assays (cellular death, autophagy, cellular migration/proliferation, platelet aggregation and angiogenesis), and obtained in a high purity grade by reversed phase chromatography. Their structures will be characterized by mass spectrometry, nuclear magnetic resonance and N-terminus sequencing. It is expected the obtention of at least 1 bioactive peptide for the synthetic analogue production through the solid phase peptide synthesis or heterologous expression at Pichia pastoris, whose action will be elucidated by toxicogenomic assays, and the toxicity will get by peripherical blood normal cells. The present work will allow the generation of new molecules at large scale, opening perspectives and reflexes to the population and study group that is insert. This way, we hope to contribute too with the knowledge area, with the elaboration of methodologies for the functional and structural characterization of never seen compounds and with the production of a new molecules with therapeutic potential against cancer. (AU)

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