Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites

Kini, R. Manjunatha; Koh, Cho Yeow

doi:10.3390/toxins8100284

Cited by 141 publications

(151 citation statements)

References 210 publications

(322 reference statements)

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“…These abundance differences likely underpin the distinct pathologies observed following envenomings by snakes found in these families. SVMPs contribute extensively to the hemorrhagic and coagulopathic venom activities following bites by viperid snakes, and the diversity of SVMPs isoforms often present in their venom likely facilitate synergistic effects, such as simultaneous action on multiple steps of the blood clotting cascade (Kini and Koh, 2016;Slagboom et al, 2017). Certain "colubrid" snakes, whether medically important or not, also show evidence of having multiple SVMP toxins in their venom, even if they do not show the sub-class diversity observed in the vipers (Mackessy and Saviola, 2016;Pla et al, 2017;Modahl et al, 2018a;Perry et al, 2018).…”

Section: Snake Venom Metalloproteinases (Svmps)mentioning

confidence: 99%

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

et al. 2019

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Animal venoms have evolved over millions of years for prey capture and defense from predators and rivals. Snake venoms, in particular, have evolved a wide diversity of peptides and proteins that induce harmful inflammatory and neurotoxic effects including severe pain and paralysis, hemotoxic effects, such as hemorrhage and coagulopathy, and cytotoxic/myotoxic effects, such as inflammation and necrosis. If untreated, many envenomings result in death or severe morbidity in humans and, despite advances in management, snakebite remains a major public health problem, particularly in developing countries. Consequently, the World Health Organization recently recognized snakebite as a neglected tropical disease that affects ∼2.7 million p.a. The major protein classes found in snake venoms are phospholipases, metalloproteases, serine proteases, and three-finger peptides. The mechanisms of action and pharmacological properties of many snake venom toxins have been elucidated, revealing a complex multifunctional cocktail that can act synergistically to rapidly immobilize prey and deter predators. However, despite these advances many snake toxins remain to be structurally and pharmacologically characterized. In this review, the multifunctional features of the peptides and proteins found in snake venoms, as well as their evolutionary histories, are discussed with the view to identifying novel modes of action and improving snakebite treatments.

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Section: Snake Venom Metalloproteinases (Svmps)mentioning

confidence: 99%

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

et al. 2019

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“…Masses of compounds that could be correlated to procoagulants ranged from 20 to 80 kDa, with the majority between 21 and 28 kDa. Compounds in this mass range most likely are SVMPs and SVSPs, which contain toxins that have previously been described to exhibit procoagulant activities in many haemotoxic snake venoms (11, 18, 73).…”

Section: Study Limitationsmentioning

confidence: 99%

“…Snake venoms consist of a mixture of different protein and peptides that are used to kill, immobilise or incapacitate their prey (11). These ‘toxins’ vary at every taxonomic level and cause a range of different toxicities, including haemotoxic, neurotoxic and/or cytotoxic pathologies (12–14).…”

Section: Introductionmentioning

confidence: 99%

“…These toxins activate the blood clotting cascade via their activity on a variety of different clotting factors, of which several are found towards the end of the clotting cascade, including factor V, factor X and prothrombin (factor II). In the same venom, it is not uncommon for other toxins to directly target fibrinogen, resulting in either its degradation or the promotion of weak fibrin clots (7, 11, 15). In addition to procoagulant toxins, snake venoms have also been reported to contain proteins with anticoagulant properties, such as phospholipases A 2 s (PLA 2 s) and C-type lectin-like proteins (16–18).…”

Section: Introductionmentioning

confidence: 99%

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High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

Slagboom

Mladic

Xie³

et al. 2019

Preprint

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17Snakebite is a neglected tropical disease that results in a variety of systemic and local pathologies in 18 envenomed victims and is responsible for around 138,000 deaths every year. Many snake venoms cause 19 severe coagulopathy that makes victims vulnerable to suffering life-threating haemorrhage. The 20 mechanisms of action of coagulopathic snake venom toxins are diverse and can result in both anticoagulant 21 and procoagulant effects. However, because snake venoms consist of a mixture of numerous protein and 22 peptide components, high throughput characterizations of specific target bioactives is challenging. In this 23 study, we applied a combination of analytical and pharmacological methods to identify snake venom toxins 24 from a wide diversity of snake species that perturb coagulation. To do so, we used a high-throughput 25 screening approach consisting of a miniaturised plasma coagulation assay in combination with a venom 26 nanofractionation approach. Twenty snake venoms were first separated using reversed-phase liquid 27 chromatography, and a post-column split allowed a small fraction to be analyzed with mass spectrometry, 28 while the larger fraction was collected and dispensed onto 384-well plates before direct analysis using a 29 plasma coagulation assay. Our results demonstrate that many snake venoms simultaneously contain both 30 procoagulant and anticoagulant bioactives that contribute to coagulopathy. In-depth identification analysis 31 from seven medically-important venoms, via mass spectrometry and nanoLC-MS/MS, revealed that 32 phospholipase A 2 toxins are frequently identified in anticoagulant venom fractions, while serine protease 33 and metalloproteinase toxins are often associated with procoagulant bioactivities. The nanofractionation 34 and proteomics approach applied herein seems likely to be a valuable tool for the rational development of 35 next-generation snakebite treatments by facilitating the rapid identification and fractionation of 36 coagulopathic toxins, thereby enabling specific targeting of these toxins by new therapeutics such as 37 monoclonal antibodies and small molecule inhibitors. Classified Personnel Information 39Author summary 40 Snakebite is a neglected tropical disease that results in more than 100,000 deaths every year. 41Haemotoxicity is one of the most common signs of systemic envenoming observed after snakebite, and 42 many snake venoms cause severe impairment of the blood coagulation that makes victims vulnerable to 43 suffering life-threating hemorrhage. In this study, we applied a combination of analytical and 44 pharmacological methods to identify snake venom toxins from a wide diversity of snake species that 45 interfere with blood coagulation. Twenty snake venoms were screened for their effects on the blood 46 coagulation cascade and based on the initial results and the medical relevance of the species, seven 47 venoms were selected for in-depth analysis of the responsible toxins using advanced identification 48 techniques. Our findings reveal a number ...

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“…Snake venom sPLA2s play roles in early-and late-onset symptomology, as well as synergistic and regulatory roles for other co-existing snake venom components [56][57][58][59][60][61][62][63]. sPLA2s are also some of the most pharmacologically active, multi-effect (neuro-myo-cyto-hemotoxic) venom components ( While sPLA2 inhibition might prove sufficient as a "bridge-to-survival" for many types of venoms when administered in a pre-referral setting and, at times, be sufficient for treatment, future SMTs might be mixtures of other SMT (Figure 3a).…”

Section: Venom Target Selectionmentioning

confidence: 99%

Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

Bulfone¹,

Samuel²,

Bickler³

et al. 2018

Preprint

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Abstract:The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential pre-referral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors and metalloprotease (MP) inhibitors.

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Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites

Cited by 141 publications

References 210 publications

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

High throughput screening and identification of coagulopathic snake venom proteins and peptides using nanofractionation and proteomics approaches

Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

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