Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms

Xie, Cuicui; Slagboom, Julien; Albulescu, Laura-Oana; Somsen, Govert W.; Vonk, Freek J.; Casewell, Nicholas R.; Kool, Jeroen

doi:10.1016/j.apsb.2020.09.005

Cited by 24 publications

(30 citation statements)

References 55 publications

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“…russelii , B . arietans , Bothrops asper , Bothrops jararaca , Calloselasma rhodostoma , and Deinagkistrodon acutus ) [ 232 , 233 ]. Furthermore, a study has demonstrated that varespladib can abrogate or delay lethality induced by presynaptically acting neurotoxic snake venom in murine models; this might in part be due to the inhibition of PLA 2 -induced anticoagulation preventing the rapid spread of the NTxs [ 9 ].…”

Section: Treatment Of Severe Animal Envenomings In the Mena Regionmentioning

confidence: 99%

“…Furthermore, a study has demonstrated that varespladib can abrogate or delay lethality induced by presynaptically acting neurotoxic snake venom in murine models; this might in part be due to the inhibition of PLA 2 -induced anticoagulation preventing the rapid spread of the NTxs [ 9 ]. Additionally, marimastat demonstrated impressive in vitro neutralization of procoagulant activities in most of these venoms, while dimercaprol and DMPS were only able to partially neutralize these activities [ 232 , 233 ]. Together, marimastat and varespladib were even able to prevent murine lethality caused by venom from the most medically important vipers of Africa, South Asia, and Central America [ 13 ].…”

Section: Treatment Of Severe Animal Envenomings In the Mena Regionmentioning

confidence: 99%

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Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

et al. 2021

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The Middle East and Northern Africa, collectively known as the MENA region, are inhabited by a plethora of venomous animals that cause up to 420,000 bites and stings each year. To understand the resultant health burden and the key variables affecting it, this review describes the epidemiology of snake, scorpion, and spider envenomings primarily based on heterogenous hospital data in the MENA region and the pathologies associated with their venoms. In addition, we discuss the venom composition and the key medically relevant toxins of these venomous animals, and, finally, the antivenoms that are currently in use to counteract them. Unlike Asia and sub-Saharan Africa, scorpion stings are significantly more common (approximately 350,000 cases/year) than snakebites (approximately 70,000 cases/year) and present the most significant contributor to the overall health burden of envenomings, with spider bites being negligible. However, this review also indicates that there is a substantial lack of high-quality envenoming data available for the MENA region, rendering many of these estimates speculative. Our understanding of the venoms and the toxins they contain is also incomplete, but already presents clear trends. For instance, the majority of snake venoms contain snake venom metalloproteinases, while sodium channel–binding toxins and potassium channel–binding toxins are the scorpion toxins that cause most health-related challenges. There also currently exist a plethora of antivenoms, yet only few are clinically validated, and their high cost and limited availability present a substantial health challenge. Yet, some of the insights presented in this review might help direct future research and policy efforts toward the appropriate prioritization of efforts and aid the development of future therapeutic solutions, such as next-generation antivenoms.

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Section: Treatment Of Severe Animal Envenomings In the Mena Regionmentioning

confidence: 99%

Section: Treatment Of Severe Animal Envenomings In the Mena Regionmentioning

confidence: 99%

Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

et al. 2021

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“…Even so, it is important to point out that upscaling by combining multiple batches may also increase costs, so the economic benefits of cell-free production would need to be reassessed. The small amounts of protein synthesized in cell-free systems could also be isolated and enriched by chromatography, as shown by the micro-fractionation of venom components [ 33 , 34 , 35 , 36 , 37 ]. However, this would also add more experimental steps, thus eliminating one of the major advantages of cell-free expression: the rapid and simple production method.…”

Section: Resultsmentioning

confidence: 99%

A Spider Toxin Exemplifies the Promises and Pitfalls of Cell-Free Protein Production for Venom Biodiscovery

Lüddecke

Paas

Talmann

et al. 2021

Toxins

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Arthropod venoms offer a promising resource for the discovery of novel bioactive peptides and proteins, but the limited size of most species translates into minuscule venom yields. Bioactivity studies based on traditional fractionation are therefore challenging, so alternative strategies are needed. Cell-free synthesis based on synthetic gene fragments is one of the most promising emerging technologies, theoretically allowing the rapid, laboratory-scale production of specific venom components, but this approach has yet to be applied in venom biodiscovery. Here, we tested the ability of three commercially available cell-free protein expression systems to produce venom components from small arthropods, using U2-sicaritoxin-Sdo1a from the six-eyed sand spider Hexophtalma dolichocephala as a case study. We found that only one of the systems was able to produce an active product in low amounts, as demonstrated by SDS-PAGE, mass spectrometry, and bioactivity screening on murine neuroblasts. We discuss our findings in relation to the promises and limitations of cell-free synthesis for venom biodiscovery programs in smaller invertebrates.

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“…In the same study, Ainsworth et al demonstrated in a murine preclinical model that EDTA was protective against the lethal effects of Echis ocellatus venom, an African viper which, similar to D. typus venom, contains a high abundance of SVMP toxins 9 , including prothrombin activators, and causes VICC in envenomed victims 23,24 . Other small molecule drugs with SVMP-inhibiting potential include other metal chelators, such as dimercaprol and DMPS (2,3-dimercapto-1-propanesulfonic acid) [25][26][27] , and the mimetic matrix metalloprotease inhibitors marimastat, batimastat and prinomastat 22,24,28 . Marimastat and batimastat were found to effectively inhibit SVMP activity and reduce haemorrhagic pathologies in murine models of E. ocellatus envenoming 24 , and inhibit the procoagulant effects of several viper venoms in vitro 24,25 .…”

Section: Introductionmentioning

confidence: 99%

“…While D. typus venom is dominated by SVMPs, PLA 2 toxins are also thought to contribute to the coagulopathy induced by this venom 29 . The small molecule drug varespladib has been extensively investigated as an inhibitor of venom PLA 2 toxins found in a wide geographical range of snake species, with such studies showing potent neutralisation of PLA 2 activity 25,27,30 and associated anticoagulant, haemorrhagic, myotoxic and neurotoxic pathologies 31–35 . Thus, small molecule treatments for snakebite have the potential to overcome the current species-specific and restrictive geographical utility of current antivenoms.…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo venom-inhibition assays identify metalloproteinase-inhibiting drugs as potential treatments for snakebite envenoming by Dispholidus typus

Menzies

Clare

Xie

et al. 2022

Preprint

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Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by Dispholidus typus (boomslang) results in venom induced consumption coagulopathy, whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for D. typus envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at $6,000/vial, typically unaffordable for most snakebite patients. We therefore investigated the in vitro and in vivo preclinical efficacy of four SVMP inhibitors to neutralise the effects of D. typus venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS. The venom of D. typus exhibited an SVMP-driven procoagulant phenotype in vitro. Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom in vitro, whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenomation, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for D. typus snakebite envenomation. These two drugs have been previously shown to be effective against Echis ocellatus venom induced consumption coagulopathy (VICC) in preclinical models, and thus we conclude that marimastat and DMPS may be valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.

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Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms

Cited by 24 publications

References 55 publications

Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

Terrestrial venomous animals, the envenomings they cause, and treatment perspectives in the Middle East and North Africa

A Spider Toxin Exemplifies the Promises and Pitfalls of Cell-Free Protein Production for Venom Biodiscovery

In vitro and in vivo venom-inhibition assays identify metalloproteinase-inhibiting drugs as potential treatments for snakebite envenoming by Dispholidus typus

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