Comparison of the primary structures, cytotoxicities, and affinities to phospholipids of five kinds of cytotoxins from the venom of Indian cobra, Naja naja

Suzuki-Matsubara, Mieko; Athauda, Senarath B. P.; Suzuki, Yoshiyuki; Matsubara, Kazumi; Moriyama, Akihiko

doi:10.1016/j.cbpc.2015.09.015

Cited by 16 publications

(13 citation statements)

References 39 publications

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“…Thus there is convergence between the two groups in upright hooding displays being associated with defensive cytotoxic function, and as they have evolved the function independently the underlying chemical mechanisms are not homologous. Hemachatus + Naja venoms have a high concentration of the cytotoxic 3FTx unique to this clade [36,37,38,39,40,41,42,43,44,45]. Similarly O. hannah venoms have the highest concentration of L-amino acid oxidase of any snake venom and also the most derived forms of venom L-amino acid oxidase [23,46,47,48,49,50,51].…”

Section: Resultsmentioning

confidence: 99%

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting

Panagides

Jackson

Ikonomopoulou

et al. 2017

Toxins

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The cytotoxicity of the venom of 25 species of Old World elapid snake was tested and compared with the morphological and behavioural adaptations of hooding and spitting. We determined that, contrary to previous assumptions, the venoms of spitting species are not consistently more cytotoxic than those of closely related non-spitting species. While this correlation between spitting and non-spitting was found among African cobras, it was not present among Asian cobras. On the other hand, a consistent positive correlation was observed between cytotoxicity and utilisation of the defensive hooding display that cobras are famous for. Hooding and spitting are widely regarded as defensive adaptations, but it has hitherto been uncertain whether cytotoxicity serves a defensive purpose or is somehow useful in prey subjugation. The results of this study suggest that cytotoxicity evolved primarily as a defensive innovation and that it has co-evolved twice alongside hooding behavior: once in the Hemachatus + Naja and again independently in the king cobras (Ophiophagus). There was a significant increase of cytotoxicity in the Asian Naja linked to the evolution of bold aposematic hood markings, reinforcing the link between hooding and the evolution of defensive cytotoxic venoms. In parallel, lineages with increased cytotoxicity but lacking bold hood patterns evolved aposematic markers in the form of high contrast body banding. The results also indicate that, secondary to the evolution of venom rich in cytotoxins, spitting has evolved three times independently: once within the African Naja, once within the Asian Naja, and once in the Hemachatus genus. The evolution of cytotoxic venom thus appears to facilitate the evolution of defensive spitting behaviour. In contrast, a secondary loss of cytotoxicity and reduction of the hood occurred in the water cobra Naja annulata, which possesses streamlined neurotoxic venom similar to that of other aquatic elapid snakes (e.g., hydrophiine sea snakes). The results of this study make an important contribution to our growing understanding of the selection pressures shaping the evolution of snake venom and its constituent toxins. The data also aid in elucidating the relationship between these selection pressures and the medical impact of human snakebite in the developing world, as cytotoxic cobras cause considerable morbidity including loss-of-function injuries that result in economic and social burdens in the tropics of Asia and sub-Saharan Africa.

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Section: Resultsmentioning

confidence: 99%

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting

Panagides

Jackson

Ikonomopoulou

et al. 2017

Toxins

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“…The P-type and S-type cytotoxins vary in their amino acid sequence at the tip of loop II: the former is characterized by the presence of Pro 31 within the phospholipid binding site near the tip of loop II, whereas the latter has Ser 29 within the same but more hydrophilic region. The binding of virtually all CTX to phospholipid membranes involves a phospholipid binding site at loop I; however, the presence of Pro 31 in P-type CTX gave rise to an additional phospholipid binding site at loop II, thus enabling the P-type CTX to exhibit higher fusion and binding activity than the S-type CTX to cell membrane (Chien et al, 1994;Suzuki-Matsubara et al, 2016). In this study, the higher potency of NS-CTX compared with NK-CTX is therefore consistent with the differential cytotoxicity reported previously for the P-type and S-type of CTX.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Snake Venoms and Cytotoxins From Two Southeast Asian Cobras (Naja sumatrana, Naja kaouthia): Exploration of Anticancer Potential, Selectivity, and Cell Death Mechanism

Chong

Tan

2020

Front. Mol. Biosci.

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Venoms of cobras ( Naja spp.) contain high abundances of cytotoxins, which contribute to tissue necrosis in cobra envenomation. The tissue-necrotizing activity of cobra cytotoxins, nevertheless, indicates anticancer potentials. This study set to explore the anticancer properties of the venoms and cytotoxins from Naja sumatrana (equatorial spitting cobra) and Naja kaouthia (monocled cobra), two highly venomous species in Southeast Asia. The cytotoxicity, selectivity, and cell death mechanisms of their venoms and cytotoxins (NS-CTX from N. sumatrana : NS-CTX; N. kaouthia : NK-CTX) were elucidated in human lung (A549), prostate (PC-3), and breast (MCF-7) cancer cell lines. Cytotoxins were purified through a sequential fractionation approach using cation-exchange chromatography, followed by C 18 reverse-phase high-performance liquid chromatography (HPLC) to homogeneity validated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and identified by liquid chromatography-tandem mass spectrometry (LCMS/MS). The cobra venoms and their respective cytotoxins exhibited concentration-dependent growth inhibitory effects in all cell lines tested, with the cytotoxins being more potent compared to the corresponding whole venoms. NS-CTX and NK-CTX are, respectively, P-type and S-type isoforms of cytotoxin, based on the amino acid sequences as per LCMS/MS analysis. Both cytotoxins exhibited differential cytotoxic effects in the cell lines tested, with NS-CTX (P-type cytotoxin) being significantly more potent in inhibiting the growth of the cancer cells. Both cytotoxins demonstrated promising selectivity only for the A549 lung cancer cell line (selectivity index = 2.17 and 2.26, respectively) but not in prostate (PC-3) and breast (MCF-7) cancer cell lines (selectivity index < 1). Flow cytometry revealed that the A549 lung cancer cells treated with NS-CTX and NK-CTX underwent necrosis predominantly. Meanwhile, the cytotoxins induced mainly caspase-independent late apoptosis in the prostate (PC-3) and breast (MCF-7) cancer cells lines but lacked selectivity. The findings revealed the limitations and challenges that could be faced during the development of new cancer therapy from cobra cytotoxins, notwithstanding their potent anticancer effects. Further studies should aim to overcome these impediments to unleash the anticancer potentials of the cytotoxins.

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“…PLA 2 s may enable and accelerate the spread of the venom after a bite via their cytolytic effects (Gutiérrez and Ownby, 2003), thus enhancing the access of other venom components to their targets. In the case of elapid snakes, PLA 2 s have also been demonstrated to potentiate the cytotoxic effect of specific 3FTxs (Suzuki-Matsubara et al, 2016) and may facilitate the rapid action of 3FTxs on their muscular and neuronal targets, leading to the onset of paralysis. Therefore, combination treatments using AChBPs, enzyme inhibitors such as varespladib, and/or antivenom should be extensively explored by the scientific community to address current therapeutic limitations associated with this lethal neglected tropical disease.…”

Section: Discussionmentioning

confidence: 99%

A Decoy-Receptor Approach Using Nicotinic Acetylcholine Receptor Mimics Reveals Their Potential as Novel Therapeutics Against Neurotoxic Snakebite

et al. 2019

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Snakebite is a neglected tropical disease that causes 138,000 deaths each year. Neurotoxic snake venoms contain small neurotoxins, including three-finger toxins (3FTxs), which can cause rapid paralysis in snakebite victims by blocking postsynaptic transmission via nicotinic acetylcholine receptors (nAChRs). These toxins are typically weakly immunogenic and thus are often not effectively targeted by current polyclonal antivenom therapies. We investigated whether nAChR mimics, also known as acetylcholine binding proteins (AChBPs), could effectively capture 3FTxs and therefore be developed as a novel class of snake-generic therapeutics for combatting neurotoxic envenoming. First, we identified the binding specificities of 3FTx from various medically important elapid snake venoms to nAChR using two recombinant nAChR mimics: the AChBP from Lymnaea stagnalis and a humanized neuronal α7 version (α7-AChBP). We next characterized these AChBP-bound and unbound fractions using SDS-PAGE and mass spectrometry. Interestingly, both mimics effectively captured long-chain 3FTxs from multiple snake species but largely failed to capture the highly related short-chain 3FTxs, suggesting a high level of binding specificity. We next investigated whether nAChR mimics could be used as snakebite therapeutics. We showed that while α7-AChBP alone did not protect against Naja haje (Egyptian cobra) venom lethality in vivo , it significantly prolonged survival times when coadministered with a nonprotective dose of antivenom. Thus, nAChR mimics are capable of neutralizing specific venom toxins and may be useful adjunct therapeutics for improving the safety and affordability of existing snakebite treatments by reducing therapeutic doses. Our findings justify exploring the future development of AChBPs as potential snakebite treatments.

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Comparison of the primary structures, cytotoxicities, and affinities to phospholipids of five kinds of cytotoxins from the venom of Indian cobra, Naja naja

Cited by 16 publications

References 39 publications

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting

How the Cobra Got Its Flesh-Eating Venom: Cytotoxicity as a Defensive Innovation and Its Co-Evolution with Hooding, Aposematic Marking, and Spitting

Cytotoxicity of Snake Venoms and Cytotoxins From Two Southeast Asian Cobras (Naja sumatrana, Naja kaouthia): Exploration of Anticancer Potential, Selectivity, and Cell Death Mechanism

A Decoy-Receptor Approach Using Nicotinic Acetylcholine Receptor Mimics Reveals Their Potential as Novel Therapeutics Against Neurotoxic Snakebite

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