Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin

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 IC50 value of 150 μM and 1021 μM for the inhibition of proteolytic and hemorrhagic activity, respectively. Independent injection experiments, with a concentration of 1600 μM of myricetin administered locally, immediately after toxin injection, demonstrated a reduction of 28±6% in the hemorrhagic lesion. Additionally, myricetin at concentrations 800, 1200 and 1600 μM promoted a reduction in plasma creatine kinase activity induced by Batx-I of 21±2%, 60±5% and 63±2%, 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.

Toxinology in Colombia: Contributions of Programa De Ofidismo/Escorpionismo and Other Research Groups

“…Moreover, these compounds inhibited the hemorrhagic, myotoxic, and edema-forming activities provoked by this toxin. Similar findings were obtained with the flavonoid myricetin (67). Nevertheless, it is important to mention that the latter studies included a new bioinformatic approach to describe the interaction between the inhibitor and the protein.…”

Attempt to Develop Rat Disseminated Intravascular Coagulation Model Using Yamakagashi (Rhabdophis tigrinus) Venom Injection

“…Easy to use. Examples of such cases have been reported include Varespradib, a specific inhibitor of Phospholipase A2, Flavonoid Myricetin for Metalloprotease, and Nafamostat for Serine protease [ 32 , 33 , 34 , 35 ]. Our rat DIC model may be a useful tool to research other therapeutic methods.…”

The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming

“…In few instances, the structural characterization of the inhibitor-toxin complex has been described via crystallography, as in the case of aristolochic acid [ 133 ], rosemarinic acid [ 134 ], and caffeic acid [ 135 ]. Moreover, docking and molecular dynamics simulations have also been used to analyze the interaction of plant-derived metabolites with snake venom PLA 2 s and SVMPs [ 136 , 137 , 138 ]. Despite abundant research in the field of plant extracts and snake venoms, to the best of our knowledge no venom-inhibitory drug derived from a plant secondary metabolite has been approved so far for clinical use in the treatment of snakebite envenomings.…”