Intravascular hemolysis induced by phospholipases A 2 from the venom of the Eastern coral snake, Micrurus fulvius : Functional profiles of hemolytic and non-hemolytic isoforms

Fernández, María Laura; Quartino, Pablo Yunes; Arce-Bejarano, Ruth; Fernández, Julián; Camacho, Luis F.; Gutiérrez, José Marı́a; Kuemmel, Daniel; Fidelio, Gerardo D.; Lomonte, Bruno

doi:10.1016/j.toxlet.2017.11.037

Cited by 22 publications

(15 citation statements)

References 42 publications

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“…On the other hand, envenomed animals developed intravascular hemolysis, as evidenced by the presence of reddish pigmented plasma one hour after envenoming, see Figure 3 C. This effect was abolished in the groups treated with the inhibitor (not shown). Myotoxicity and intravascular hemolysis in envenomings by M. fulvius in animal models are due to the action of venom PLA2s [ 37 ], which explains the beneficial effect of the drug.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, in the dichotomic pattern described for Micrurus venoms from the proteomic standpoint, i.e., PLA2-rich and alpha-neurotoxin-rich venoms [ 40 ], M. fulvius fits within the first group. In addition, besides neurotoxicity (the primary toxicity in humans) other toxic activities associated with this venom are witnessed in different animal species (e.g., myotoxicity and intravascular hemolysis) and are also caused by the action of PLA2s [ 37 ]. This largely explains the success of these potent PLA2 inhibitors in abrogating lethality, myonecrosis, and hemolysis in our experiments in pigs.…”

Section: Discussionmentioning

confidence: 99%

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Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

Lewin

Gilliam

et al. 2018

Toxins

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There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake’s bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

Lewin

Gilliam

et al. 2018

Toxins

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“…Venomous PLA2 is known to induce severe intravascular hemolysis and lethality in vivo. [14,29] In this study, a mortality rate of 100 % was observed in mice that received 1.0 mg kg À1 free PLA2 (Figure 4 A). In contrast, when mice were injected with the same dosage of free PLA2 followed by L&K-NPs (2.5 mg kg À1 , L&K-NP:PLA2 = 2.5:1), 5 out of 6 mice survived, suggesting…”

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confidence: 56%

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

et al. 2020

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Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K‐NP”). The L&K‐NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in‐coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K‐NP structure, which voids toxicity associated with free molecules. In the study, L&K‐NPs effectively inhibit PLA2‐induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K‐NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K‐NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti‐PLA2 approach.

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“…Indirect hemolytic activities in sheep blood were also reported for PLA 2 from B. alternatus at 47.26 µM [35]. However, a study involving the isolation of two PLA 2 (PLA 2 -12 and PLA 2 -17), from the snake Micrurus fulvius, showed that one of the enzymes showed intravascular hemolytic activity in a mice model, namely PLA 2 -17, while PLA 2 -12 did not show intravascular hemolysis in the same model tested [46]. This last result corroborates our findings.…”

Section: Discussionmentioning

confidence: 87%

Antibiofilm Activity of Acidic Phospholipase Isoform Isolated from Bothrops erythromelas Snake Venom

Nunes

Frihling

Barros

et al. 2020

Toxins

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Introduction: Bacterial resistance is a worldwide public health problem, requiring new therapeutic options. An alternative approach to this problem is the use of animal toxins isolated from snake venom, such as phospholipases A2 (PLA2), which have important antimicrobial activities. Bothropserythromelas is one of the snake species in the northeast of Brazil that attracts great medical-scientific interest. Here, we aimed to purify and characterize a PLA2 from B. erythromelas, searching for heterologous activities against bacterial biofilms. Methods: Venom extraction and quantification were followed by reverse-phase high-performance liquid chromatography (RP-HPLC) in C18 column, matrix-assisted ionization time-of-flight (MALDI-ToF) mass spectrometry, and sequencing by Edman degradation. All experiments were monitored by specific activity using a 4-nitro-3-(octanoyloxy) benzoic acid (4N3OBA) substrate. In addition, hemolytic tests and antibacterial tests including action against Escherichiacoli, Staphylococcusaureus, and Acinetobacterbaumannii were carried out. Moreover, tests of antibiofilm action against A. baumannii were also performed. Results: PLA2, after one purification step, presented 31 N-terminal amino acid residues and a molecular weight of 13.6564 Da, with enzymatic activity confirmed in 0.06 µM concentration. Antibacterial activity against S. aureus (IC50 = 30.2 µM) and antibiofilm activity against A. baumannii (IC50 = 1.1 µM) were observed. Conclusions: This is the first time that PLA2 purified from B. erythromelas venom has appeared as an alternative candidate in studies of new antibacterial medicines.

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Intravascular hemolysis induced by phospholipases A 2 from the venom of the Eastern coral snake, Micrurus fulvius : Functional profiles of hemolytic and non-hemolytic isoforms

Cited by 22 publications

References 42 publications

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

Antibiofilm Activity of Acidic Phospholipase Isoform Isolated from Bothrops erythromelas Snake Venom

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