Structural and pharmacological comparison of daboiatoxin from<i>Daboia russelli siamensis</i>with viperotoxin F and vipoxin from other vipers

Gopalan, Gayathri; Thwin, Maung Maung; Gopalakrishnakone, P.; Swaminathan, Kunchithapadam

doi:10.1107/s0907444907016204

Cited by 18 publications

(10 citation statements)

References 29 publications

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“…Fourteen conserved cysteines of sPLA 2 form seven disulfide bridges that stabilize the tertiary structure. These proteins share a homologous core and invariant tertiary structure [27,28] that in- Fig. (1).…”

Section: Structure Of Phospholipases a 2 S (Pla 2 S)mentioning

confidence: 99%

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

Samy¹,

Gopalakrishnakone²,

Stiles³

et al. 2012

Current Medicinal Chemistry

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The majority of snake venom phospholipases A(2) (svPLA(2)s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in β-sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium- dependent catalytic mechanism. Additionally, svPLA(2)s display an array of biological actions that are either dependent or independent of catalysis. The PLA(2)s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gram-negatives by svPLA(2) requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic- based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA(2)s, which include "fatal depolarization" of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA(2)s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA(2)-derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA(2)s is bactericidal. Thus identification of the bactericidal sites in svPLA(2)s has potential for developing novel antimicrobials.

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Section: Structure Of Phospholipases a 2 S (Pla 2 S)mentioning

confidence: 99%

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

Samy¹,

Gopalakrishnakone²,

Stiles³

et al. 2012

Current Medicinal Chemistry

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“…While envenoming by Chinese D. siamensis has not been reported to produce clinically evident neurotoxicity, we have shown the venom displays pre-synaptic neurotoxicity and myotoxicity in the chick biventer cervicis nerve-muscle preparation [ 34 ]. These activities of the venoms from Daboia species have been attributed to the presence of PLA 2 s, both clinically and in vitro [ 13 , 15 , 18 , 32 , 35 , 36 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

Lay

Liang²,

Hodgson³

2023

Toxins

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The venom of the Russell’s viper (Daboia siamensis) contains neurotoxic and myotoxic phospholipase A2 toxins which can cause irreversible damage to motor nerve terminals. Due to the time delay between envenoming and antivenom administration, antivenoms may have limited efficacy against some of these venom components. Hence, there is a need for adjunct treatments to circumvent these limitations. In this study, we examined the efficacy of Chinese D. siamensis antivenom alone, and in combination with a PLA2 inhibitor, Varespladib, in reversing the in vitro neuromuscular blockade in the chick biventer cervicis nerve-muscle preparation. Pre-synaptic neurotoxicity and myotoxicity were not reversed by the addition of Chinese D. siamensis antivenom 30 or 60 min after venom (10 µg/mL). The prior addition of Varespladib prevented the neurotoxic and myotoxic activity of venom (10 µg/mL) and was also able to prevent further reductions in neuromuscular block and muscle twitches when added 60 min after venom. The addition of the combination of Varespladib and antivenom 60 min after venom failed to produce further improvements than Varespladib alone. This demonstrates that the window of time in which antivenom remains effective is relatively short compared to Varespladib and small-molecule inhibitors may be effective in abrogating some activities of Chinese D. siamensis venom.

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“…These effects are likely to be attributable to the PLA 2 component(s) of the venom. PLA 2 activity in Daboia species venoms has previously been reported [ 7 , 10 , 12 , 14 ], and Tan et al [ 16 ] confirmed the presence of putative PLA 2 toxins in Guangxi D. siamensis venom. However, it is uncertain whether the PLA 2 toxins of D. siamensis venom are responsible for in vitro myotoxic effects.…”

Section: Discussionmentioning

confidence: 71%

“…However, other clinical outcomes, including local swelling, blistering ecchymosis, hypopituitarism, generalised capillary permeability, neurotoxicity, and myotoxicity, are geographically disjunct [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Comparative proteomic studies elucidated the diverse composition of Daboia species venoms from different regions of South-East Asia, supporting the variable clinical effects observed following snake envenomation from different locations [ 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 77%

“…PLA 2 pre-synaptic neurotoxins and myotoxins are toxins that make up a major component of many snake venoms, including Russell’s viper, and can explain the venom activities of Chinese venom. Examples of biochemically characterised pre-synaptic PLA 2 toxins include Daboiatoxin from Myanmar D. siamensis [ 12 , 14 , 15 ], Viperotoxin F from Taiwan D. siamensis formensis [ 7 , 12 , 19 ], and U1-viperotoxin-Dr1a and U1-viperotoxin-Dr1b from Sri Lankan D. russelii [ 10 ]. Pre-synaptic PLA 2 s from Thai D. siamensis venom have previously been identified as Russtoxin, but it is suggested they share a very similar pharmacological and structural profile to Viperotoxin F. It is logical to conclude that Chinese D. siamensis venom may be compositionally similar to Thai venom and Daboia species alike, suggesting that D. siamensis snakebite in Chinese regions may benefit from the clinical use of Chinese or possibly Thai D. siamensis antivenom.…”

Section: Discussionmentioning

confidence: 99%

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In Vitro Toxicity of Chinese Russell’s Viper (Daboia siamensis) Venom and Neutralisation by Antivenoms

Lay

Liang

Hodgson

2022

Toxins

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Daboia siamensis (Russell’s viper) is a highly venomous and medically important snake in China, as well as much of Asia. There is minimal information on the pharmacological activity of the venom of the Chinese species, and currently no commercially available specific antivenom in China. This has led to the use of non-specific antivenoms to treat D. siamensis envenomation. In this study, the in vitro neurotoxicity and myotoxicity of D. siamensis venom was examined and the efficacy of four antivenoms was investigated, including the recently developed Chinese D. siamensis monovalent antivenom (C-DsMAV) and three commercially available antivenoms (Thai D. siamensis (Thai-DsMAV) monovalent antivenom, Deinagkistrodon acutus monovalent antivenom (DaAV), and Gloydius brevicaudus monovalent antivenom (GbAV). D. siamensis venom (10–30 µg/mL) caused the concentration-dependent inhibition of indirect twitches in the chick biventer cervicis nerve muscle preparation, without abolishing contractile responses to exogenous agonists ACh or CCh, indicating pre-synaptic neurotoxicity. Myotoxicity was also evident at these concentrations with inhibition of direct twitches, an increase in baseline tension, and the partial inhibition of ACh, CCh, and KCl responses. The prior addition of C-DsMAV or Thai-DsMAV prevented the neurotoxic and myotoxic activity of D. siamensis venom (10 µg/mL). The addition of non-specific antivenoms (GbAV and DaAV) partially prevented the neurotoxic activity of venom (10 µg/mL) but failed to neutralize the myotoxic effects. We have shown that D. siamensis venom exhibits in vitro weak presynaptic neurotoxicity and myotoxicity, which can be prevented by the pre-addition of the Chinese and Thai Russell’s viper antivenoms. Non-specific antivenoms were poorly efficacious. There should be further development of a monospecific antivenom against D. siamensis envenomation in China.

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Structural and pharmacological comparison of daboiatoxin fromDaboia russelli siamensiswith viperotoxin F and vipoxin from other vipers

Cited by 18 publications

References 29 publications

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

Snake Venom Phospholipases A2: A Novel Tool Against Bacterial Diseases

In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell’s Viper (Daboia siamensis) Venom Toxicity

In Vitro Toxicity of Chinese Russell’s Viper (Daboia siamensis) Venom and Neutralisation by Antivenoms

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