Convergent evolution of defensive venom components in spitting cobras

Kazandjian, Taline D.; Petras, Daniel; Robinson, Sam; Undheim, Eivind A.B.; Arbuckle, Kevin; Whiteley, Gareth; Albulescu, Laura-Oana; Ainsworth, Stuart; Wagstaff, Simon C.; Wüster, Wolfgang; Harrison, Robert A.; Vetter, Irina; Calvete, Juan J.; Casewell, Nicholas R.

doi:10.1016/j.toxicon.2019.12.059

Cited by 4 publications

(11 citation statements)

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“…While reductions in cytotoxic potency observed with D. russelii were minor, N. haje venom was significantly less cytotoxic than all other venoms, including those from the congeneric spitting cobra species N. nigricollis and N. pallida; however, this observation is in line with the distinct, predominantly neurotoxic, composition and functional activity of this nonspitting cobra venom 56,57 . As an additional pharmacological measure, the Hill slopes of all venoms were calculated and compared (Fig.…”

Section: Discussionmentioning

confidence: 69%

“…These findings were unexpected given the extensive variation in toxin composition among these snake species 9,56 . While reductions in cytotoxic potency observed with D. russelii were minor, N. haje venom was significantly less cytotoxic than all other venoms, including those from the congeneric spitting cobra species N. nigricollis and N. pallida; however, this observation is in line with the distinct, predominantly neurotoxic, composition and functional activity of this non-spitting cobra venom 56,57 . As an additional pharmacological measure, the Hill slopes of all venoms were calculated and compared ( Fig.…”

Section: Discussionmentioning

confidence: 90%

“…1). These findings were unexpected given the extensive variation in toxin composition among these snake species 9,56 .…”

Section: Discussionmentioning

confidence: 92%

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Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Hall

Rasmussen²,

Dawson

et al. 2022

Preprint

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Morbidity from snakebite envenoming affects approximately 400,000 people annually. Tissue damage at the bite-site often leaves victims with catastrophic life-long injuries and is largely untreatable by currently available antivenoms. Repurposing small molecule drugs that inhibit specific snake venom toxins offers a potential new treatment strategy for tackling this neglected tropical disease. Using human skin cell assays as an initial model for snakebite-induced dermonecrosis, we show that the repurposed drugs 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat, and varespladib, alone or in combination, reduce the cytotoxic potency of a broad range of medically important snake venoms up to 5.7-fold. Thereafter, using a preclinical murine model of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib potently inhibit the dermonecrotic activity of three geographically distinct and medically important snake venoms. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 90%

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Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Hall

Rasmussen²,

Dawson

et al. 2022

Preprint

Self Cite

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“…The ability of the antivenoms to neutralise PLA 2 activity correlates well with the in vivo ED 50 data -SAIMR Polyvalent performs best, followed by Panafrican and then PANAF. As we previously demonstrated in Figure 4 that all the antivenoms performed equally well at restoring plasma clotting, the differences in the in vivo antivenom ED 50 s may therefore be mediated by PLA 2 activity, and these toxins are known to potentiate the pathological effects of other toxins found in spitting elapid venoms (25).…”

Section: Venom Phospholipase A2 Activity and Neutralisation By The An...mentioning

confidence: 63%

“…That said, the three antivenoms exhibited similar efficacy in neutralising the lethal effects of N. mossambica venom on mice (in vivo ED50 results), though this activity may perhaps not be mediated by PLA2s. The major toxin families in H. haemachatus venom are cytotoxic three-finger toxins (3FTx) and PLA2 (22,25) which produce neurotoxic and cytotoxic clinical pathologies. The Eswatini H. haemachatus venom exhibited an anticoagulant phenotype and strong PLA2 activity in vitro, which is in agreement with previous studies of this venom from South African specimens, which attributed the 3FTx protein family as the primary driver of anticoagulant phenotype of H. haemachatus venom (22).…”

Section: Discussionmentioning

confidence: 99%

Two snakebite antivenoms have potential to reduce Eswatini’s dependency upon a single, increasingly unavailable product: results of preclinical efficacy testing

Menzies

Litschka-Koen

Edge

et al. 2022

Preprint

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Background: Snakebite is a major public health concern in Eswatini, where treatment relies upon one antivenom – SAIMR Polyvalent. Although effective in treating snakebite, SAIMR Polyvalent is difficult to source outside its manufacturing country (South Africa) and is dau ntingly expensive. We compared the preclinical venom-neutralising efficacy of two alternative antivenoms and SAIMR Polyvalent against the lethal and tissue-destructive effects of venoms from five species of medically important snakes using in vivo murine assays. The test antivenoms were 'Panafrican' manufactured by Instituto Clodomiro Picado and 'PANAF' manufactured by Premium Serums & Vaccines. Principal Findings: In vivo murine preclinical studies identified both test antivenoms were equally or more effective than SAIMR Polyvalent at neutralising lethal and tissue-destructive effects of Naja mossambica venom. Both test antivenoms were less effective than SAIMR Polyvalent at neutralising the lethal effects of Bitis arietans, Dendroaspis polylepis, Hemachatus haemachatus and Naja annulifera venoms, but similarly effective at neutralising tissue damage induced by B. arietans and H. haemachatus venoms. In vitro immunological assays identified that IgG titres and toxin-specificities of the test antivenoms were comparable to SAIMR Polyvalent. Plasma clotting disturbances by H. haemachatus and N. mossambica were effectively neutralised by the test antivenoms, whereas SAIMR Polyvalent failed to neutralise this bioactivity of N. mossambica venom. The SVMP activity of B. arietans venom was equally reduced by all three antivenoms. The PLA 2 activities of H. haemachatus and N. mossambica were effectively neutralised by all three antivenoms. Conclusions: Panafrican outperformed PANAF, though both were less poly-specifically effective than SAIMR Polyvalent. The efficacy of these antivenoms against the lethal and tissue-destructive effects of N. mossambica venom, the most common biting species in Eswatini, identify that Panafrican and PANAF antivenoms offer effective alternatives to SAIMR for the treatment of snakebite in Eswatini, and potentially for neighbouring countries.

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Venom-derived pain-causing toxins: insights into sensory neuron function and pain mechanisms

Robinson

Deuis

Klasfauseweh

et al. 2022

PAIN

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Convergent evolution of defensive venom components in spitting cobras

Cited by 4 publications

References 0 publications

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms

Two snakebite antivenoms have potential to reduce Eswatini’s dependency upon a single, increasingly unavailable product: results of preclinical efficacy testing

Venom-derived pain-causing toxins: insights into sensory neuron function and pain mechanisms

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