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A global strategy, under the coordination of the World Health Organization, is being unfolded to reduce the impact of snakebite envenoming. One of the pillars of this strategy is to ensure safe and effective treatments. The mainstay in the therapy of snakebite envenoming is the administration of animal-derived antivenoms. In addition, new therapeutic options are being explored, including recombinant antibodies and natural and synthetic toxin inhibitors. In this review, snake venom toxins are classified in terms of their abundance and toxicity, and priority actions are being proposed in the search for snake venom metalloproteinase (SVMP), phospholipase A2 (PLA2), three-finger toxin (3FTx), and serine proteinase (SVSP) inhibitors. Natural inhibitors include compounds isolated from plants, animal sera, and mast cells, whereas synthetic inhibitors comprise a wide range of molecules of a variable chemical nature. Some of the most promising inhibitors, especially SVMP and PLA2 inhibitors, have been developed for other diseases and are being repurposed for snakebite envenoming. In addition, the search for drugs aimed at controlling endogenous processes generated in the course of envenoming is being pursued. The present review summarizes some of the most promising developments in this field and discusses issues that need to be considered for the effective translation of this knowledge to improve therapies for tackling snakebite envenoming.
José Gutiérrez; Laura-Oana Albulescu; Rachel Clare; Nicholas Casewell; Tarek Abd El-Aziz; Teresa Escalante; Alexandra Rucavado. The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming. Toxins 2021, 13, 451 .
AMA StyleJosé Gutiérrez, Laura-Oana Albulescu, Rachel Clare, Nicholas Casewell, Tarek Abd El-Aziz, Teresa Escalante, Alexandra Rucavado. The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming. Toxins. 2021; 13 (7):451.
Chicago/Turabian StyleJosé Gutiérrez; Laura-Oana Albulescu; Rachel Clare; Nicholas Casewell; Tarek Abd El-Aziz; Teresa Escalante; Alexandra Rucavado. 2021. "The Search for Natural and Synthetic Inhibitors That Would Complement Antivenoms as Therapeutics for Snakebite Envenoming." Toxins 13, no. 7: 451.
The intravenous administration of polyclonal antibodies known as antivenom is the only effective treatment for snakebite envenomed victims, but because of inter-specific variation in the toxic components of snake venoms, these therapies have variable efficacies against different snake species and/or different populations of the same species. In this study, we sought to characterize the in vitro venom binding capability and in vitro cross-neutralizing activity of antivenom, specifically the Hemato Polyvalent antivenom (HPAV; The Queen Saovabha Memorial Institute (QSMI) of the Thai Red Cross Society, Thailand) and three monovalent antivenoms (QSMI) specific to Daboia siamensis, Calloselasma rhodostoma, and Trimeresurus albolabris venoms, against a variety of South Asian and Southeast Asian viper venoms (Calloselasma rhodostoma, Daboia russelii, Hypnale hypnale, Trimeresurus albolabris, Trimeresurus purpureomaculatus, Trimeresurus hageni, and Trimeresurus fucatus). Using ELISA and immunoblotting approaches, we find that the majority of protein components in the viper venoms were recognized and bound by the HPAV polyvalent antivenom, while the monospecific antivenom made against T.albolabris extensively recognized toxins present in the venom of related species, T. purpureomaculatus, T. hageni, and T. fucatus. In vitro coagulation assays using bovine plasma revealed similar findings, with HPAV antivenom significantly inhibiting the coagulopathic activities of all tested viper venoms and T. albolabris antivenom inhibiting the venoms from Malaysian arboreal pit vipers. We also show that the monovalent C. rhodostoma antivenom exhibits highly comparable levels of immunological binding and in vitro venom neutralization to venom from both Thailand and Malaysia, despite previous reports of considerable intraspecific venom variation. Our findings suggest that Thai antivenoms from QSMI may by useful therapeutics for managing snake envenomings caused by a number of Southeast Asian viper species and populations for which no specific antivenom currently exists and thus should be explored further to assess their clinical utility in treating snakebite victims.
Janeyuth Chaisakul; Muhamad Rusdi Ahmad Rusmili; Jaffer Alsolaiss; Laura-Oana Albulescu; Robert A. Harrison; Iekhsan Othman; Nicholas R. Casewell. In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms. Toxins 2020, 12, 766 .
AMA StyleJaneyuth Chaisakul, Muhamad Rusdi Ahmad Rusmili, Jaffer Alsolaiss, Laura-Oana Albulescu, Robert A. Harrison, Iekhsan Othman, Nicholas R. Casewell. In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms. Toxins. 2020; 12 (12):766.
Chicago/Turabian StyleJaneyuth Chaisakul; Muhamad Rusdi Ahmad Rusmili; Jaffer Alsolaiss; Laura-Oana Albulescu; Robert A. Harrison; Iekhsan Othman; Nicholas R. Casewell. 2020. "In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms." Toxins 12, no. 12: 766.
Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.
Chunfang Xie; Laura-Oana Albulescu; Mátyás A. Bittenbinder; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines 2020, 8, 297 .
AMA StyleChunfang Xie, Laura-Oana Albulescu, Mátyás A. Bittenbinder, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Jeroen Kool. Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins. Biomedicines. 2020; 8 (9):297.
Chicago/Turabian StyleChunfang Xie; Laura-Oana Albulescu; Mátyás A. Bittenbinder; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. 2020. "Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins." Biomedicines 8, no. 9: 297.
Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib on snake venom PLA2s was investigated by nanofractionation analytics, which combined chromatography, mass spectrometry (MS), and bioassays. The venoms of the medically important snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus, Echis ocellatus, and Oxyuranus scutellatus were separated by liquid chromatography (LC) followed by nanofractionation and interrogation of the fractions by a coagulation assay and a PLA2 assay. Next, we assessed the ability of varespladib to inhibit the activity of enzymatic PLA2s and the coagulopathic toxicities induced by fractionated snake venom toxins, and identified these bioactive venom toxins and those inhibited by varespladib by using parallel recorded LC-MS data and proteomics analysis. We demonstrated here that varespladib was not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities (most profoundly anticoagulation) induced by venom toxins. While varespladib effectively inhibited PLA2 toxins responsible for anticoagulant effects, we also found some evidence that this inhibitory molecule can partially abrogate procoagulant venom effects caused by different toxin families. These findings further emphasize the potential clinical utility of varespladib in mitigating the toxic effects of certain snakebites.
Chunfang Xie; Laura-Oana Albulescu; Kristina B. M. Still; Julien Slagboom; Yumei Zhao; Zhengjin Jiang; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes. Biomedicines 2020, 8, 165 .
AMA StyleChunfang Xie, Laura-Oana Albulescu, Kristina B. M. Still, Julien Slagboom, Yumei Zhao, Zhengjin Jiang, Govert W. Somsen, Freek J. Vonk, Nicholas R. Casewell, Jeroen Kool. Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes. Biomedicines. 2020; 8 (6):165.
Chicago/Turabian StyleChunfang Xie; Laura-Oana Albulescu; Kristina B. M. Still; Julien Slagboom; Yumei Zhao; Zhengjin Jiang; Govert W. Somsen; Freek J. Vonk; Nicholas R. Casewell; Jeroen Kool. 2020. "Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes." Biomedicines 8, no. 6: 165.
Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent coagulopathic toxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combination of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.
Chunfang Xie; Laura Albulescu; Matyas A Bittenbinder; Govert Somsen; Freek Vonk; Nicholas R Casewell; Jeroen Kool. Neutralizing effects of small molecule inhibitors and metal chelators on coagulopathic Viperinae snake venom toxins. 2020, 1 .
AMA StyleChunfang Xie, Laura Albulescu, Matyas A Bittenbinder, Govert Somsen, Freek Vonk, Nicholas R Casewell, Jeroen Kool. Neutralizing effects of small molecule inhibitors and metal chelators on coagulopathic Viperinae snake venom toxins. . 2020; ():1.
Chicago/Turabian StyleChunfang Xie; Laura Albulescu; Matyas A Bittenbinder; Govert Somsen; Freek Vonk; Nicholas R Casewell; Jeroen Kool. 2020. "Neutralizing effects of small molecule inhibitors and metal chelators on coagulopathic Viperinae snake venom toxins." , no. : 1.
Snakebite is a medical emergency causing high mortality and morbidity in rural tropical communities that typically experience delayed access to unaffordable therapeutics. Viperid snakes are responsible for the majority of envenomings, but extensive interspecific variation in venom composition dictates that different antivenom treatments are used in different parts of the world, resulting in clinical and fiscal snakebite management challenges. Here, we show that a number of repurposed Phase 2-approved small molecules are capable of broadly neutralizing distinct viper venom bioactivities in vitro by inhibiting different enzymatic toxin families. Furthermore, using multiple in vivo models of envenoming, we demonstrate that a single dose of a rationally-selected dual inhibitor combination consisting of marimastat and varespladib prevents lethality caused by venom from the most medically-important vipers of Africa, South Asia and Central America. Our findings strongly support the translation of combinations of safe and affordable enzyme inhibitors as novel broad-spectrum therapeutics for snakebite.
Laura-Oana Albulescu; Chunfang Xie; Stuart Ainsworth; Jaffer Alsolaiss; Edouard Crittenden; Charlotte A. Dawson; Rowan Softley; Keirah E. Bartlett; Robert A. Harrison; Jeroen Kool; Nicholas R. Casewell. A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite. 2020, 1 .
AMA StyleLaura-Oana Albulescu, Chunfang Xie, Stuart Ainsworth, Jaffer Alsolaiss, Edouard Crittenden, Charlotte A. Dawson, Rowan Softley, Keirah E. Bartlett, Robert A. Harrison, Jeroen Kool, Nicholas R. Casewell. A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite. . 2020; ():1.
Chicago/Turabian StyleLaura-Oana Albulescu; Chunfang Xie; Stuart Ainsworth; Jaffer Alsolaiss; Edouard Crittenden; Charlotte A. Dawson; Rowan Softley; Keirah E. Bartlett; Robert A. Harrison; Jeroen Kool; Nicholas R. Casewell. 2020. "A therapeutic combination of two small molecule toxin inhibitors provides pancontinental preclinical efficacy against viper snakebite." , no. : 1.
Venomous snakebite is one of the world’s most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused by the multitude of injected toxins. In this study, the coagulopathic toxicities of venoms from the medically relevant snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus and Echis ocellatus were assessed. The venoms were separated by liquid chromatography (LC) followed by nanofractionation and parallel mass spectrometry (MS). A recently developed high-throughput coagulation assay was employed to assess both the pro- and anticoagulant activity of separated venom toxins. The neutralization capacity of antivenoms on separated venom components was assessed and the coagulopathic venom peptides and enzymes that were either neutralized or remained active in the presence of antivenom were identified by correlating bioassay results with the MS data and with off-line generated proteomics data. The results showed that most snake venoms analyzed contained both procoagulants and anticoagulants. Most anticoagulants were identified as phospholipases A2s (PLA2s) and most procoagulants correlated with snake venom metalloproteinases (SVMPs) and serine proteases (SVSPs). This information can be used to better understand antivenom neutralization and can aid in the development of next-generation antivenom treatments.
Chunfang Xie; Julien Slagboom; Laura-Oana Albulescu; Ben Bruyneel; Kristina B. M. Still; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics. Toxins 2020, 12, 53 .
AMA StyleChunfang Xie, Julien Slagboom, Laura-Oana Albulescu, Ben Bruyneel, Kristina B. M. Still, Freek J. Vonk, Govert W. Somsen, Nicholas R. Casewell, Jeroen Kool. Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics. Toxins. 2020; 12 (1):53.
Chicago/Turabian StyleChunfang Xie; Julien Slagboom; Laura-Oana Albulescu; Ben Bruyneel; Kristina B. M. Still; Freek J. Vonk; Govert W. Somsen; Nicholas R. Casewell; Jeroen Kool. 2020. "Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics." Toxins 12, no. 1: 53.