Russell’s viper venom: from diagnostic to bypassing agent for hemophilia?

Venomous snakes produce various toxic components to incapacitate prey and defend against predators. Venom toxins are mainly peptides and proteins that have evolved to act with high efficacy on essential biological processes effectuating specific toxicities (eg, cardiotoxicity, neurotoxicity, and coagulotoxicity). Given their high specificity and bioactivity, snake venom toxins are at the basis of a multitude of biomedical applications, including diagnostic tools and therapeutic approaches. So far, 6 snake venom-derived drugs have been approved for clinical use [ [1] Bordon K.C.F. Cologna C.T. Fornari-Baldo E.C. Pinheiro-Júnior E.L. Cerni F.A. Amorim F.G. Anjolette F.A.P. Cordeiro F.A. Wiezel G.A. Cardoso I.A. Ferreira I.G. de Oliveira I.S. Boldrini-França J. Pucca M.B. Baldo M.A. Arantes E.C. From animal poisons and venoms to medicines: achievements, challenges and perspectives in drug discovery. Front Pharmacol. 2020; 11: 1132 Crossref Scopus (95) Google Scholar ]. Although most are synthetic toxin analogs, cobratide and batroxobin come as toxins directly purified from snake venom. Cobratide (also known as cobrotoxin) is a short-chain postsynaptic α-neurotoxin purified from Chinese or Taiwan Cobra (Naja atra) venom. As a specific ligand for the α1 subunit of the muscle nicotinic acetylcholine receptor, cobratide produces strong analgesic effects and suppresses various types of chronic pain [ [2] Gazerani P. Cairns B.E. Venom-based biotoxins as potential analgesics. Expert Rev Neurother. 2014; 14: 1261-1274 Crossref Scopus (24) Google Scholar ]. Batroxobin (also known as hemocoagulase, reptilase, or botropase) is a serine protease purified from the venom of the Lancehead snakes Bothrops atrox and Bothrops moojeni. It cleaves off fibrinopeptide A from the Aα-chain of fibrinogen, resulting in fibrin strands that cannot complete the full extent of “knob-hole” interactions that typically occur following the thrombin-proteolyzed release of fibrinopeptides A and B [ [3] Pieters M. Wolberg A.S. Fibrinogen and fibrin: an illustrated review. Res Pract Thromb Haemost. 2019; 3: 161-172 Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar ]. Moreover, the fibrin strands are not cross-linked as batroxobin does not activate factor XIII (FXIII). Because of its defibrinogenating effect, batroxobin is used as an anticoagulant for the management of vascular disorders, such as acute ischemic stroke, among others [ [4] Serrano S.M.T. The long road of research on snake venom serine proteinases. Toxicon. 2013; 62: 19-26 Crossref PubMed Scopus (136) Google Scholar ]. In addition, diagnostic assays make use of batroxobin to (indirectly) assess the presence of thrombin inhibitors or fibrinogen concentration and/or function [ [5] Moore G.W. Snake venoms in diagnostic hemostasis and thrombosis. Semin Thromb Hemost. 2022; 48: 145-160 Crossref Scopus (5) Google Scholar ].