Varespladib (LY315920) neutralises phospholipase A2 mediated prothrombinase-inhibition induced by Bitis snake venoms

Youngman, Nicholas J.; Walker, Andrew A.; Naude, Arno; Coster, Kristian; Sundman, Eric; Fry, Bryan G.

doi:10.1016/j.cbpc.2020.108818

Cited by 32 publications

(26 citation statements)

References 22 publications

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“…This study is congruent with prior work, demonstrating the efficacy of varespladib against a wide range of snake venom PLA 2 -driven pathophysiological actions (20,26,30,(32)(33)(34)(43)(44)(45)(46)(47)(48), thereby underscoring the potential utility of this compound as a first-aid option. For instance, field treatment options such as varespladib could stabilize patients in remote locations while being transported to hospital, and or serve as the only treatment option for some snake species such as the potent FXa-inhibiting anticoagulant effect of the African spitting cobra venoms included in this study (18,24,26,(49)(50)(51).…”

Section: Resultssupporting

confidence: 88%

“…We also ascertained the ability of prinomastat to cross-react with the anticoagulant PLA 2 of these medically important snakes. In addition to undertaking the first anticoagulant toxicity testing for N. ashei, N. katiensis, and N. nubiae venoms, this work builds upon increasingly popular research into non-immunoglobulin treatments for snakebites using temperature-stable small molecule inhibitors (SMIs) that may improve snakebite firstaid in remote areas (20,26,(30)(31)(32)(33)(34). Therefore, our results hopefully inform and streamline future platform testing while minimizing the need for in vivo animal testing.…”

Section: Introductionmentioning

confidence: 94%

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The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

et al. 2021

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African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A2 (Group I PLA2) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta, N. nigricollis, and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei, N. katiensis, and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei, N. katiensis, and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA2 (Group II PLA2). In this study prinomastat inhibited the FXa-inhibiting PLA2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 94%

The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

et al. 2021

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“…All components with detected enzymatic PLA 2 activities were identified as PLA 2 toxins and were fully neutralized by the small molecule toxin inhibitor varespladib. We demonstrated here that varespladib inhibited many of the anticoagulant bioactivities of the toxin components found in these venoms, similar to findings recently described by others for certain snakes of the genera Naja, Pseudechis and Bitis [16,37,38], and we confirmed that the toxins responsible are likely to be PLA 2 s based on correlations between MS and proteomics data and the bioactivity chromatograms. However, we also revealed that several of the procoagulant venom toxins were also neutralized to some degree by varespladib.…”

Section: Discussionsupporting

confidence: 91%

Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes

et al. 2020

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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.

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“…The ability of the small molecule PLA 2 inhibitor varespladib to inhibit the anticoagulant activity of N. nigricollis venom is consistent with findings from the literature demonstrating the neutralization of PLA 2 -mediated coagulopathy of the venoms of several vipers [ 51 , 52 , 53 , 54 ], the elapid Oxyanurus scutellatus [ 51 ], and many Afro-Asian elapids [ 34 ] by varespladib. Varespladib binds to the fatty acid substrate site in PLA 2 [ 55 ], which would explain its inhibition of the enzymatic component of the anti-coagulant action of acidic and basic PLA 2 s, but in this way it may also prevent basic PLA 2 binding to Factor Xa through steric hindrance, thus also inhibiting this particular mechanism of anti-coagulation.…”

Section: Discussionsupporting

confidence: 85%

Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib

Kazandjian

Arrahman

Still

et al. 2021

Toxins

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Bites from elapid snakes typically result in neurotoxic symptoms in snakebite victims. Neurotoxins are, therefore, often the focus of research relating to understanding the pathogenesis of elapid bites. However, recent evidence suggests that some elapid snake venoms contain anticoagulant toxins which may help neurotoxic components spread more rapidly. This study examines the effects of venom from the West African black-necked spitting cobra (Naja nigricollis) on blood coagulation and identifies potential coagulopathic toxins. An integrated RPLC-MS methodology, coupled with nanofractionation, was first used to separate venom components, followed by MS, proteomics and coagulopathic bioassays. Coagulation assays were performed on both crude and nanofractionated N. nigricollis venom toxins as well as PLA2s and 3FTx purified from the venom. Assays were then repeated with the addition of either the phospholipase A2 inhibitor varespladib or the snake venom metalloproteinase inhibitor marimastat to assess whether either toxin inhibitor is capable of neutralizing coagulopathic venom activity. Subsequent proteomic analysis was performed on nanofractionated bioactive venom toxins using tryptic digestion followed by nanoLC-MS/MS measurements, which were then identified using Swiss-Prot and species-specific database searches. Varespladib, but not marimastat, was found to significantly reduce the anticoagulant activity of N. nigricollis venom and MS and proteomics analyses confirmed that the anticoagulant venom components mostly consisted of PLA2 proteins. We, therefore, conclude that PLA2s are the most likely candidates responsible for anticoagulant effects stimulated by N. nigricollis venom.

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Varespladib (LY315920) neutralises phospholipase A2 mediated prothrombinase-inhibition induced by Bitis snake venoms

Cited by 32 publications

References 22 publications

The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms

Varespladib Inhibits the Phospholipase A2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes

Anticoagulant Activity of Naja nigricollis Venom Is Mediated by Phospholipase A2 Toxins and Inhibited by Varespladib

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