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Neutralising Effects of Small Molecule Toxin Inhibitors on Nanofractionated Coagulopathic Crotalinae Snake Venoms

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Neutralising Effects of Small Molecule Toxin Inhibitors on Nanofractionated Coagulopathic Crotalinae Snake Venoms + MODEL Acta Pharmaceutica Sinica B xxxx;xxx(xxx):xxx Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B www.elsevier.com/locate/apsb www.sciencedirect.com ORIGINAL ARTICLE Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms Chunfang Xiea,b, Julien Slagbooma,b, Laura-Oana Albulescuc,d, Govert W. Somsena,b, Freek J. Vonka,b,e, Nicholas R. Casewellc,d, Jeroen Koola,b,* aAmsterdam Institute of Molecular and Life Sciences, Division of BioAnalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam 1081HV, the Netherlands bCentre for Analytical Sciences Amsterdam (CASA), Amsterdam 1098 XH, the Netherlands cCentre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK dCentre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK eNaturalis Biodiversity Center, Leiden 2333 CR, the Netherlands Received 12 July 2020; received in revised form 3 September 2020; accepted 4 September 2020 KEY WORDS Abstract Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhi- Snakebite; biting effects of the small molecules varespladib (nonspecific phospholipase A inhibitor), marimastat Antivenom; 2 (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulo- Varespladib; Marimastat; pathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jar- Dimercaprol; araca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, Chelators; followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions Nanofractionation of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly Abbreviations: ACN, acetonitrile; CTL, C-type lectins; DMSO, dimethyl sulfoxide; FA, formic acid; HTS, high-throughput screening; LC, liquid chromatography; MS, mass spectrometry; NOI, no observed inhibition; PBS, phosphate buffered saline; PLA2, phospholipase A2; PN, partly neutralised at 20 mmol/L inhibitor concentrations; SVMP, snake venom metalloproteinase; SVSP, snake venom serine protease; TIC, total ion current; WHO, World Health Organization; XIC, extracted ion current. *Corresponding author. Amsterdam Institute of Molecular and Life Sciences, Division of BioAnalytical Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, 1081HV, the Netherlands. Tel.: þ31 20 5987542. E-mail address: [email protected] (Jeroen Kool). Peer review under responsibility of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. https://doi.org/10.1016/j.apsb.2020.09.005 2211-3835 ª 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Xie Chunfang et al., Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms, Acta Pharmaceutica Sinica B, https://doi.org/10.1016/j.apsb.2020.09.005 + MODEL 2 Chunfang Xie et al. identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Con- trastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and high- lights their potential as future snakebite treatments. ª 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction proteolytically degrade fibrinogen and regulate factor V and plasminogen to perturb haemostasis19,20. SVMPs can activate Snake envenoming is a highly relevant public health issue that prothrombin and/or factor X, hydrolyse and degrade endothelial causes substantial morbidity and mortality in tropical regions cell basement membranes, and preclude muscle fibre regeneration, (more than 138,000 deaths every year)1, but remains largely all of which may contribute to perturbations of blood coagulation neglected by funding bodies, public health authorities, the phar- and induce severe haemorrhaging21. These enzymes can poten- maceutical industry and health advocacy groups2. The true burden tially be inhibited by small molecule toxin inhibitors, such as the 22e24 of snakebite remains unknown, although it has been estimated to PLA2 inhibitor varespladib and the metalloproteinase inhib- 3 17,25,26 be as high as 1,841,000 envenomings annually . However, since itor marimastat . Varespladib, which is a nonspecific PLA2 many tropical snakebite victims first seek traditional treatment inhibitor and was a drug candidate for treating atherosclerotic rather than presenting at a healthcare facility, this number may be lesions27, coronary heart disease28,29, and acute chest syndrome an underestimate, as it is known that many snakebite victims die at induced by sickle cell disease23, has been the focus of consider- home and those deaths remain unrecorded2,4. Specific antivenom able recent research as a potential therapeutic candidate for therapies, which consist of immunoglobulins purified from serum snakebite treatment13,14,22,24. Varespladib has showed efficient 13,22 or plasma of animals following hyperimmunization by selected inhibition of venom-induced PLA2 activity and has been venom(s), represent life-threatening treatments of snake enve- demonstrated to reduce haemorrhage, myotoxicity and neurotox- noming5. They are given intravenously in a clinical environment icity in murine models after snake envenomation13,24, as well as and can neutralise the coagulopathic, haemorrhagic and hypo- protect against venom-induced lethality caused by certain snake tensive actions of snake venoms, among other signs of systemic species and, thus, is now considered as a potential pre-referral envenoming6. However, antivenoms are highly specific in neu- drug candidate for treating snakebite22. tralising only one or several venoms from species of a certain Similarly, other small molecule inhibitor-based antidote can- geographical location7,8, due to extensive variation in venom didates have been studied for their potential to inhibit SVMP and composition among different snake species9. In addition, SVSP toxin families, and therefore serve as alternative (or antivenom-associated adverse reactions are common10, with both adjunct), non-antibody based, future treatments for snakebite7,30. acute reactions (anaphylactic shock or immediate hypersensitiv- One such molecule is marimastat, which is a water-soluble broad ity) and delayed reactions (treatment-induced serum sickness) spectrum matrix metalloprotease inhibitor31,32, and which binds to reported11. Finally, antivenoms are often limited in terms of their the active site of matrix metalloproteinases to form non-covalent availability and/or poorly distributed, and are typically unafford- complexes17,33. Hence it is considered as a potential inhibitor of able to those who live in impoverished rural regions of the SVMPs which share regions of structural similarity to matrix tropicsdi.e., those who are at the greatest risk of snakebite12. metalloproteinases26,34,35. Marimastat has been evaluated for in- A promising approach for solving the critical therapeutic gap hibition of angiogenesis36 and the spread and growth of can- between a snakebite occurring and delayed presentation to a cers25,32. Because SVMP toxins are major constituents of many hospital setting, is the use of small molecule toxin inhibitors that snake venoms, marimastat was repurposed as a candidate to treat can be administered orally and are able to (at least partially) snake envenomation and has since been shown to effectively neutralise enzymatic snake venom toxicities13e17. The venoms of inhibit the metalloprotease activity of snake venoms in vitro and many snakes, particularly those of vipers (Viperinae and Crotali- neutralise systemic toxicity and lethality in vivo in mice enve- nae; both family Viperidae) cause coagulopathic and haemor- nomed with viper venoms17,37. rhagic toxicities by the combined actions of different toxin SVMPs are Zn2þ-dependent proteinases, which become inac- 2þ 38 isoforms of enzymatic families, such as phospholipase A2s tive after Zn removal from their active site . Many metal (PLA2s), snake venom serine proteases (SVSPs), and snake venom chelator treatments have been proven to be safe in humans and are metalloproteinases (SVMPs)6,7. Snake
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