Abstract
Most of the snakebite envenomations in Central and South America are caused by species belonging to Bothrops genus. Their venom is composed mainly by zinc-dependent metalloproteinases, responsible of the hemorrhage characteristic of these envenomations. The aim of this study was to determine the inhibitory ability of ten flavonoids on the in-vitro proteolytic activity of Bothrops atrox venom and on the hemorrhagic, edema-forming and myonecrotic activities of Batx-I, the most abundant metalloproteinase isolated from this venom. Myricetin was the most active compound, exhibiting an IC value of 150 M and 1021 M for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 M of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 M promoted a reduction in plasma creatine kinase activity induced by Batx-I of , and , respectively. Molecular dynamics simulations coupled with the adaptive biasing method suggest that myricetin can bind to the metalloproteinase active site via formation of hydrogen bonds between the hydroxyl groups 3’, 4’ and 5’ of the benzyl moiety and amino acid Glu143 of the metalloproteinase. The hydroxyl substitution pattern of myricetin appears to be essential for its inhibitory activity. Based on this evidence, myricetin constitutes a candidate for the development of inhibitors to reduce local tissue damage in snakebite envenomations.
Highlights
Snakebites are an important public health problem affecting approximately 1.8–2.2 million people annually, resulting in 81,000–138,000 deaths [1]
The snake venom metalloproteinases (SVMPs) represent one of the most abundant components of the snake venoms of Viperidae family [7]. These enzymes are large multi-domain proteins which are classified into three major classes (P-I, P-II and P-III) based on the presence of various domains and their organization [8]. They are responsible for the hemorrhage, local edema, myonecrosis, inflammation and dermonecrosis induced by viperid snake envenomations [9,10]
All flavonoids inhibited the proteolytic activity of B. atrox venom on fluorescein conjugates of gelatin (Figure 2)
Summary
Snakebites are an important public health problem affecting approximately 1.8–2.2 million people annually, resulting in 81,000–138,000 deaths [1]. In Latin America, the Bothrops genus (Viperidae) inflicts the vast majority of these bites, among which the lance-head vipers B. asper and B. atrox are medically relevant in Central and South America [2,3] These envenomations are characterized by local pathological alterations associated with edema, myonecrosis, dermonecrosis, blistering, hemorrhage and systemic alterations such as coagulopathies, acute renal failure and cardiovascular shock which occur in moderate and severe cases [3]. The SVMPs represent one of the most abundant components of the snake venoms of Viperidae family [7] These enzymes are large multi-domain proteins which are classified into three major classes (P-I, P-II and P-III) based on the presence of various domains and their organization [8]. They are responsible for the hemorrhage, local edema, myonecrosis, inflammation and dermonecrosis induced by viperid snake envenomations [9,10]
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