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Anticoagulant activity of black snake (Elapidae: Pseudechis) venoms: Mechanisms, potency, and antivenom efficacy.
Toxicol Lett. 2020 May 19; 330:176-184.TL

Abstract

Venoms from Pseudechis species (Australian black snakes) within the Elapidae family are rich in anticoagulant PLA2 toxins, with the exception of one species (P. porphyriacus) that possesses procoagulant mutated forms of the clotting enzyme Factor Xa. Previously the mechanism of action of the PLA2 toxins' anticoagulant toxicity was said to be due to inhibition of Factor Xa, but this statement was evidence free. We conducted a series of anticoagulation assays to elucidate the mechanism of anticoagulant action produced by P. australis venom. Our results revealed that, rather than targeting FXa, the PLA2 toxins inhibited the prothrombinase complex, with FVa-alone or as part of the prothrombinase complex-as the primary target; but with significant thrombin inhibition also noted. In contrast, FXa, and other factors inhibited only to a lesser degree were minor targets. We quantified coagulotoxic effects upon human plasma caused by all nine anticoagulant Pseudechis species, including nine localities of P. australis across Australia, and found similar anticoagulant potency across all Pseudechis species, with greater potency in P. australis and the undescribed Pseudechis species in the NT. In addition, the northern localities and eastern of P. australis were significantly more potent than the central, western, and southern localities. All anticoagulant venoms responded well to Black Snake Antivenom, except P. colletti which was poorly neutralised by Black Snake Antivenom and also Tiger Snake Antivenom (the prescribed antivenom for this species). However, we found LY315920 (trade name: Varespladib), a small molecule inhibitor of PLA2 proteins, exhibited strong potency against P. colletti venom. Thus, Varespladib may be a clinically viable treatment for anticoagulant toxicity exerted by this species that is not neutralised by available antivenoms. Our results provide insights into coagulotoxic venom function, and suggest future in vivo work be conducted to progress the development of a cheaper, first-line treatment option to treat PLA2-rich snake venoms globally.

Authors+Show Affiliations

Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia; Australian School of Herpetology, Southport, QLD, Australia.Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.Venom Supplies Pty Ltd, Stonewell Rd, Tanunda, SA, 5352, Australia.Venom Supplies Pty Ltd, Stonewell Rd, Tanunda, SA, 5352, Australia.Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia.Venom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, QLD, 4072, Australia. Electronic address: bgfry@uq.edu.au.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32442717

Citation

Zdenek, Christina N., et al. "Anticoagulant Activity of Black Snake (Elapidae: Pseudechis) Venoms: Mechanisms, Potency, and Antivenom Efficacy." Toxicology Letters, vol. 330, 2020, pp. 176-184.
Zdenek CN, Youngman NJ, Hay C, et al. Anticoagulant activity of black snake (Elapidae: Pseudechis) venoms: Mechanisms, potency, and antivenom efficacy. Toxicol Lett. 2020;330:176-184.
Zdenek, C. N., Youngman, N. J., Hay, C., Dobson, J., Dunstan, N., Allen, L., Milanovic, L., & Fry, B. G. (2020). Anticoagulant activity of black snake (Elapidae: Pseudechis) venoms: Mechanisms, potency, and antivenom efficacy. Toxicology Letters, 330, 176-184. https://doi.org/10.1016/j.toxlet.2020.05.014
Zdenek CN, et al. Anticoagulant Activity of Black Snake (Elapidae: Pseudechis) Venoms: Mechanisms, Potency, and Antivenom Efficacy. Toxicol Lett. 2020 May 19;330:176-184. PubMed PMID: 32442717.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anticoagulant activity of black snake (Elapidae: Pseudechis) venoms: Mechanisms, potency, and antivenom efficacy. AU - Zdenek,Christina N, AU - Youngman,Nicholas J, AU - Hay,Chris, AU - Dobson,James, AU - Dunstan,Nathan, AU - Allen,Luke, AU - Milanovic,Leontina, AU - Fry,Bryan G, Y1 - 2020/05/19/ PY - 2019/12/18/received PY - 2020/05/05/revised PY - 2020/05/11/accepted PY - 2020/5/23/pubmed PY - 2020/5/23/medline PY - 2020/5/23/entrez KW - Anticoagulant KW - Black snakes KW - Coagulopathy KW - Coagulotoxins KW - Pseudechis KW - Varespladib KW - Venom SP - 176 EP - 184 JF - Toxicology letters JO - Toxicol. Lett. VL - 330 N2 - Venoms from Pseudechis species (Australian black snakes) within the Elapidae family are rich in anticoagulant PLA2 toxins, with the exception of one species (P. porphyriacus) that possesses procoagulant mutated forms of the clotting enzyme Factor Xa. Previously the mechanism of action of the PLA2 toxins' anticoagulant toxicity was said to be due to inhibition of Factor Xa, but this statement was evidence free. We conducted a series of anticoagulation assays to elucidate the mechanism of anticoagulant action produced by P. australis venom. Our results revealed that, rather than targeting FXa, the PLA2 toxins inhibited the prothrombinase complex, with FVa-alone or as part of the prothrombinase complex-as the primary target; but with significant thrombin inhibition also noted. In contrast, FXa, and other factors inhibited only to a lesser degree were minor targets. We quantified coagulotoxic effects upon human plasma caused by all nine anticoagulant Pseudechis species, including nine localities of P. australis across Australia, and found similar anticoagulant potency across all Pseudechis species, with greater potency in P. australis and the undescribed Pseudechis species in the NT. In addition, the northern localities and eastern of P. australis were significantly more potent than the central, western, and southern localities. All anticoagulant venoms responded well to Black Snake Antivenom, except P. colletti which was poorly neutralised by Black Snake Antivenom and also Tiger Snake Antivenom (the prescribed antivenom for this species). However, we found LY315920 (trade name: Varespladib), a small molecule inhibitor of PLA2 proteins, exhibited strong potency against P. colletti venom. Thus, Varespladib may be a clinically viable treatment for anticoagulant toxicity exerted by this species that is not neutralised by available antivenoms. Our results provide insights into coagulotoxic venom function, and suggest future in vivo work be conducted to progress the development of a cheaper, first-line treatment option to treat PLA2-rich snake venoms globally. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/32442717/Anticoagulant_activity_of_black_snake__Elapidae:_Pseudechis__venoms:_Mechanisms_potency_and_antivenom_efficacy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(20)30147-8 DB - PRIME DP - Unbound Medicine ER -
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