Development of an original antiophidic agent with a broad functional spectrum and interspecific character

• Grant number: 21/01463-0
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2022
• Effective date (End): May 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Toxicology
• Valor Concedido/Desembolsado (R$): 223,850.88 / 59,354.40
• Principal Investigator: Marcos Roberto de Mattos Fontes
• Grantee: Fábio Florença Cardoso
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

Snakebites are a public health problem, concerning tropical and subtropical regions, rural and poor areas of Latin America, Africa, Asia and Oceania. In Brazil, Bothrops and Crotalus genera account for about 98% of reported snakebites. Bothropic envenomation is characterized by intense local myonecrosis (and other local effects) inefficiently neutralized by antivenom, which can induce slight or severe reactions to the victims. Meanwhile, Crotalid envenomation is characterized by systemic effects, but has lethality up to 6 times higher than other snakebites. A class of myotoxic proteins found in these venoms which is structurally similar to phospholipases A2 (PLA2s), known as PLA2-like toxins, 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. Moreover, metalloproteinases (SVMPs) with hemorrhagic activity aggravate this condition, promoting muscle damage indirectly by ischemia on the affected region. In this context, there are evidences that several cinnamic acid derivatives are inhibitors of these toxic effects. Therefore, we propose to perform the synthesis of new molecules from the modification of these cinnamic acid derivatives in order to obtain inhibitors that are more efficient and with biotechnological/therapeutic potential. The inhibitory efficiency of these modifications will be screened in myography (contractile process), morphology (muscle fibers and hemorrhagic halo) and calorimetry (affinity to toxins) methods. The molecular mechanisms of inhibition by these modifications will be evaluated by crystallography and simulations (molecular dynamics). Thus, we look for an original pharmacological prototype for a neglected tropical disease promoted by different species of snakes.