Neutralization of a bothropic PLA2-like protein by caftaric acid, a novel potent inhibitor of ophidian myotoxicity

• Published in: Biochimie Vol. 170; pp. 163 - 172
• Main Authors: Cardoso, Fábio F., Gomes, Antoniel A.S., Dreyer, Thiago R., Cavalcante, Walter L.G., Dal Pai, Maeli, Gallacci, Márcia, Fontes, Marcos R.M.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.03.2020
• Subjects: Bothropic snake; Caftaric acid; Myotoxicity; Phospholipase A2-like toxin; Plant compound; Snake venom; Bothropic snake; Snake venom; Phospholipase A2-like toxin; Caftaric acid; Plant compound; Myotoxicity
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2020.01.010

Envenoming by snakebite is an important global health issue that has received little attention, leading the World Health Organization to naming it as neglected tropical disease. Several snakebites present serious local symptoms manifested on victims that may not be efficiently neutralized by serum therapy. Phospholipase A2-like (PLA2-like) toxins are present in Viperidae venoms and are responsible for local myotoxic activity. Herein, we investigated the association between BthTX-I toxin and caftaric acid (CFT), a molecule present in plants. CFT neutralized neuromuscular blocking and muscle-damaging activities promoted by BthTX-I. Calorimetric and light-scattering assays demonstrated that CFT inhibitor interacted with dimeric BthTX-I. Bioinformatics simulations indicated that CFT inhibitor binds to the toxin’s hydrophobic channel (HCh). According to the current myotoxic mechanism, three different regions of PLA2-like toxins have specific tasks: protein allosteric activation (HCh), membrane dockage (MDoS), and membrane rupture (MDiS). We propose CFT inhibitor interferes with the allosteric activation, which is related to the conformation change leading to the exposure/alignment of MDoS/MDiS region. This is the first report of a PLA2-like toxin fully inhibited by a compound that interacts only with its HCh region. Thus, CFT is a novel candidate to complement serum therapy and improve the treatment of snakebite. •Caftaric acid neutralizes the myotoxic effects promoted by a PLA2-like protein.•Affinity assays demonstrate that inhibitor interacts with the toxin.•Caftaric acid is the first full inhibitor that binds only into hydrophobic channel.•The inhibitor prevents the allosteric activation of the toxin.•The data presented are in agreement with the accepted myotoxic mechanism for PLA2-like proteins.