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| Author(s): |
Fábio Florença Cardoso
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Botucatu. 2017-08-29. |
| Institution: | Universidade Estadual Paulista (Unesp). Instituto de Biociências. Botucatu |
| Defense date: | 2016-03-01 |
| Advisor: | Marcos Roberto de Mattos Fontes |
| Abstract | |
Snakebites are a public health problem, concerning tropical and subtropical regions, rural and poor areas of Latin America, Africa, Asia and Oceania countries. In Brazil, Bothrops genus accounts for about 90% of reported snakebites, whose envenomation is characterized by intense local myonecrosis inefficiently neutralized by antivenom. A class of myotoxic proteins found in Bothrops venoms which is structurally similar to phospholipases A2 (PLA2), is responsible for inducing muscle injuries by a non-catalytic mechanism, partially explained by different hypotheses. However, there are evidences that myotoxic and in vitro paralyzing effects are due to their destabilizing-membrane activity and they act in synergy with the catalytic PLA2 myotoxins in envenomation. In this study, it was developed a new protocol for purification of a non-catalytic botropic myotoxin (PLA2 homologues or PLA2-like proteins) BthTX-I, which was evaluated by crystallographic, calorimetric, myographic and morphologic assays. Potential plant inhibitors of cinnamates class were co-crystallized with BthTX-I and tested to inhibit in vitro paralysis and muscle injuries promoted by the toxin. Among all the compounds tested, the chicoric and caftaric acids presented excellent BthTX-I inhibition characteristiscs. However, only chicoric acid (CA) we were able to perform crystallographic experiments, which presented different structural characteristics compared to other ligands and bothropic toxins. According to the latest proposals of the structural components involved in the activity of PLA2 homologue myotoxins, as well as by the interface presented between BthTX-I and AC, it was possible to propose that the interaction between protein and the inhibitor leads to tetrameric oligomerization, preventing the alignment between both in membrane-docking site (MDoS) and membrane-disrupting site (MDiS). (AU) | |
| FAPESP's process: | 12/07112-6 - Structural and functional studies with Bothropstoxin-I, from Bothrops jararacussu snake venom, and caffeic acid derivates |
| Grantee: | Fábio Florença Cardoso |
| Support Opportunities: | Scholarships in Brazil - Doctorate |