Research

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15 pages, 1568 KiB

Open AccessArticle

Research into the Bioengineering of a Novel α-Conotoxin from the Milked Venom of Conus obscurus

by Sean Wiere, Christopher Sugai, Michael J. Espiritu, Vincent P. Aurelio, Chloe D. Reyes, Nicole Yuzon, Randy M. Whittal, Jan Tytgat, Steve Peigneur and Jon-Paul Bingham

Int. J. Mol. Sci. 2022, 23(20), 12096; https://doi.org/10.3390/ijms232012096 - 11 Oct 2022

Cited by 2 | Viewed by 1337

Abstract

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing [...] Read more.

The marine cone snail produces one of the fastest prey strikes in the animal kingdom. It injects highly efficacious venom, often causing prey paralysis and death within seconds. Each snail has hundreds of conotoxins, which serve as a source for discovering and utilizing novel analgesic peptide therapeutics. In this study, we discovered, isolated, and synthesized a novel α3/5-conotoxins derived from the milked venom of Conus obscurus (α-conotoxin OI) and identified the presence of α-conotoxin SI-like sequence previously found in the venom of Conus striatus. Five synthetic analogs of the native α-conotoxin OI were generated. These analogs incorporated single residue or double residue mutations. Three synthetic post-translational modifications (PTMs) were synthetically incorporated into these analogs: N-terminal truncation, proline hydroxylation, and tryptophan bromination. The native α-conotoxin OI demonstrated nanomolar potency in Poecilia reticulata and Homosapiens muscle-type nicotinic acetylcholine receptor (nAChR) isoforms. Moreover, the synthetic α-[P9K] conotoxin OI displayed enhanced potency in both bioassays, ranging from a 2.85 (LD₅₀) to 18.4 (IC₅₀) fold increase in comparative bioactivity. The successful incorporation of PTMs, with retention of both potency and nAChR isoform selectivity, ultimately pushes new boundaries of peptide bioengineering and the generation of novel α-conotoxin-like sequences. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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14 pages, 3013 KiB

Open AccessArticle

Equipped for Sexual Stings? Male-Specific Venom Peptides in Euscorpius italicus

by Jonas Krämer, Ricardo Pommerening and Reinhard Predel

Int. J. Mol. Sci. 2022, 23(19), 11020; https://doi.org/10.3390/ijms231911020 - 20 Sep 2022

Cited by 1 | Viewed by 1468

Abstract

In the animal kingdom, intraspecific variation occurs, for example, between populations, different life stages, and sexes. For venomous animals, this can involve differences in their venom composition. In cases where venom is utilized in the context of mating, the differences in composition might [...] Read more.

In the animal kingdom, intraspecific variation occurs, for example, between populations, different life stages, and sexes. For venomous animals, this can involve differences in their venom composition. In cases where venom is utilized in the context of mating, the differences in composition might be driven by sexual selection. In this regard, the genus Euscorpius is a promising group for further research, as some of these scorpions exhibit a distinct sexual dimorphism and are known to perform a sexual sting during mating. However, the venom composition of this genus remains largely unexplored. Here, we demonstrate that Euscorpius italicus exhibits a male-specific venom composition, and we identify a large fraction of the substances involved. The sex specificity of venom peptides was first determined by analyzing the presence/absence patterns of ion signals in MALDI-TOF mass spectra of venom samples from both sexes and juveniles. Subsequently, a proteo-transcriptomic analysis provided sequence information on the relevant venom peptides and their corresponding precursors. As a result, we show that several potential toxin precursors are down-regulated in male venom glands, possibly to reduce toxic effects caused to females during the sexual sting. We have identified the precursor of one of the most prominent male-specific venom peptides, which may be an ideal candidate for activity tests in future studies. In addition to the description of male-specific features in the venom of E. italicus, this study also includes a general survey of venom precursors in this species. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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18 pages, 3398 KiB

Open AccessArticle

Pharmacological Screening of Venoms from Five Brazilian Micrurus Species on Different Ion Channels

by Jessica Matos Kleiz-Ferreira, Hans Bernaerts, Ernesto Lopes Pinheiro-Junior, Steve Peigneur, Russolina Benedeta Zingali and Jan Tytgat

Int. J. Mol. Sci. 2022, 23(14), 7714; https://doi.org/10.3390/ijms23147714 - 13 Jul 2022

Cited by 1 | Viewed by 1744

Abstract

Coral snake venoms from the Micrurus genus are a natural library of components with multiple targets, yet are poorly explored. In Brazil, 34 Micrurus species are currently described, and just a few have been investigated for their venom activities. Micrurus venoms are composed [...] Read more.

Coral snake venoms from the Micrurus genus are a natural library of components with multiple targets, yet are poorly explored. In Brazil, 34 Micrurus species are currently described, and just a few have been investigated for their venom activities. Micrurus venoms are composed mainly of phospholipases A₂ and three-finger toxins, which are responsible for neuromuscular blockade—the main envenomation outcome in humans. Beyond these two major toxin families, minor components are also important for the global venom activity, including Kunitz-peptides, serine proteases, 5′ nucleotidases, among others. In the present study, we used the two-microelectrode voltage clamp technique to explore the crude venom activities of five different Micrurus species from the south and southeast of Brazil: M. altirostris, M. corallinus, M. frontalis, M. carvalhoi and M. decoratus. All five venoms induced full inhibition of the muscle-type α1β1δε nAChR with different levels of reversibility. We found M. altirostris and M. frontalis venoms acting as partial inhibitors of the neuronal-type α7 nAChR with an interesting subsequent potentiation after one washout. We discovered that M. altirostris and M. corallinus venoms modulate the α1β2 GABA_AR. Interestingly, the screening on K_V1.3 showed that all five Micrurus venoms act as inhibitors, being totally reversible after the washout. Since this activity seems to be conserved among different species, we hypothesized that the Micrurus venoms may rely on potassium channel inhibitory activity as an important feature of their envenomation strategy. Finally, tests on Na_V1.2 and Na_V1.4 showed that these channels do not seem to be targeted by Micrurus venoms. In summary, the venoms tested are multifunctional, each of them acting on at least two different types of targets. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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23 pages, 13317 KiB

Open AccessArticle

Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway

by Fei Bai, Yongbo Song, Yi Cao, Mengqi Ban, Zhenyu Zhang, Yang Sun, Yuan Feng and Chunli Li

Int. J. Mol. Sci. 2022, 23(13), 7065; https://doi.org/10.3390/ijms23137065 - 25 Jun 2022

Cited by 1 | Viewed by 1676

Abstract

Trigeminal neuralgia (TN) is a common type of peripheral neuralgia in clinical practice, which is usually difficult to cure. Common analgesic drugs are difficult for achieving the desired analgesic effect. Syb-prII-1 is a β-type scorpion neurotoxin isolated from the scorpion venom of Buthus [...] Read more.

Trigeminal neuralgia (TN) is a common type of peripheral neuralgia in clinical practice, which is usually difficult to cure. Common analgesic drugs are difficult for achieving the desired analgesic effect. Syb-prII-1 is a β-type scorpion neurotoxin isolated from the scorpion venom of Buthus martensi Karsch (BmK). It has an important influence on the voltage-gated sodium channel (VGSCs), especially closely related to Nav1.8 and Nav1.9. To explore whether Syb-prII-1 has a good analgesic effect on TN, we established the Sprague Dawley (SD) rats’ chronic constriction injury of the infraorbital nerve (IoN-CCI) model. Behavioral, electrophysiological, Western blot, and other methods were used to verify the model. It was found that Syb-prII-1 could significantly relieve the pain behavior of IoN-CCI rats. After Syb-prII-1 was given, the phosphorylation level of the mitogen-activated protein kinases (MAPKs) pathway showed a dose-dependent decrease after IoN-CCI injury. Moreover, Syb-prII-1(4.0 mg/kg) could significantly change the steady-state activation and inactivation curves of Nav1.8. The steady-state activation and inactivation curves of Nav1.9 were similar to those of Nav1.8, but there was no significant difference. It was speculated that it might play an auxiliary role. The binding mode, critical residues, and specific interaction type of Syb-prII-1 and VSD2^rNav1.8 were clarified with computational simulation methods. Our results indicated that Syb-prII-1 could provide a potential treatment for TN by acting on the Nav1.8 target. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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16 pages, 3474 KiB

Open AccessArticle

Molecular Characterization of a New Tetrodotoxin-Binding Protein, Peroxiredoxin-1, from Takifugu bimaculatus

by Kun Qiao, Chunchun Wang, Luqiang Huang, Huimin Feng, Bei Chen, Min Xu, Yongchang Su, Shuji Liu, Nan Pan, Jie Su and Zhiyu Liu

Int. J. Mol. Sci. 2022, 23(6), 3071; https://doi.org/10.3390/ijms23063071 - 12 Mar 2022

Cited by 3 | Viewed by 2176

Abstract

Pufferfish are considered a culinary delicacy but require careful preparation to avoid ingestion of the highly toxic tetrodotoxin (TTX), which accumulates in certain tissues. In this study, the tissue distribution of peroxiredoxin-1 from Takifugu bimaculatus was investigated. The peroxiredoxin-1 protein was obtained by [...] Read more.

Pufferfish are considered a culinary delicacy but require careful preparation to avoid ingestion of the highly toxic tetrodotoxin (TTX), which accumulates in certain tissues. In this study, the tissue distribution of peroxiredoxin-1 from Takifugu bimaculatus was investigated. The peroxiredoxin-1 protein was obtained by in vitro recombinant expression and purification. The recombinant protein had a strong ability to scavenge hydroxyl radicals, protect superhelical DNA plasmids from oxidative damage, and protect L929 cells from H₂O₂ toxicity through in vitro antioxidant activity. In addition, we verified its ability to bind to tetrodotoxin using surface plasmon resonance techniques. Further, recombinant proteins were found to facilitate the entry of tetrodotoxin into cells. Through these analyses, we identified, for the first time, peroxiredoxin-1 protein from Takifugu bimaculatus as a potential novel tetrodotoxin-binding protein. Our findings provide a basis for further exploration of the application of peroxiredoxin-1 protein and the molecular mechanisms of tetrodotoxin enrichment in pufferfish. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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14 pages, 2430 KiB

Open AccessArticle

Anti-HIV Activity of Snake Venom Phospholipase A2s: Updates for New Enzymes and Different Virus Strains

by Andrei Siniavin, Svetlana Grinkina, Alexey Osipov, Vladislav Starkov, Victor Tsetlin and Yuri Utkin

Int. J. Mol. Sci. 2022, 23(3), 1610; https://doi.org/10.3390/ijms23031610 - 30 Jan 2022

Cited by 8 | Viewed by 3124

Abstract

Since the beginning of the HIV epidemic, lasting more than 30 years, the main goal of scientists was to develop effective methods for the prevention and treatment of HIV infection. Modern medicines have reduced the death rate from AIDS by 80%. However, they [...] Read more.

Since the beginning of the HIV epidemic, lasting more than 30 years, the main goal of scientists was to develop effective methods for the prevention and treatment of HIV infection. Modern medicines have reduced the death rate from AIDS by 80%. However, they still have side effects and are very expensive, dictating the need to search for new drugs. Earlier, it was shown that phospholipases A2 (PLA2s) from bee and snake venoms block HIV replication, the effect being independent on catalytic PLA2 activity. However, the antiviral activity of human PLA2s against Lentiviruses depended on catalytic function and was mediated through the destruction of the viral membrane. To clarify the role of phospholipolytic activity in antiviral effects, we analyzed the anti-HIV activity of several snake PLA2s and found that the mechanisms of their antiviral activity were similar to that of mammalian PLA2. Our results indicate that snake PLA2s are capable of inhibiting syncytium formation between chronically HIV-infected cells and healthy CD4-positive cells and block HIV binding to cells. However, only dimeric PLA2s had pronounced virucidal and anti-HIV activity, which depended on their catalytic activity. The ability of snake PLA2s to inactivate the virus may provide an additional barrier to HIV infection. Thus, snake PLA2s might be considered as candidates for lead molecules in anti-HIV drug development. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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19 pages, 3121 KiB

Open AccessArticle

Cross Pharmacological, Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom

by Sonia Maatoug, Amani Cheikh, Oussema Khamessi, Hager Tabka, Zied Landoulsi, Jean-Marie Guigonis, Sylvie Diochot, Saïd Bendahhou and Rym Benkhalifa

Int. J. Mol. Sci. 2021, 22(22), 12290; https://doi.org/10.3390/ijms222212290 - 13 Nov 2021

Viewed by 2342

Abstract

The voltage-gated K⁺ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In [...] Read more.

The voltage-gated K⁺ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In the present study, we focused on the biochemical and pharmacological characterization of the component in AahG50 scorpion venom that potently and selectively blocks the Kv3.1 channels. We used a combined optimization through advanced biochemical purification and patch-clamp screening steps to characterize the peptide in AahG50 active on Kv3.1 channels. We described the inhibitory effect of a toxin on Kv3.1 unitary current in black lipid bilayers. In silico, docking experiments are used to study the molecular details of the binding. We identified the first scorpion venom peptide inhibiting Kv3.1 current at 170 nM. This toxin is the alpha-KTx 15.1, which occludes the Kv3.1 channel pore by means of the lysine 27 lateral chain. This study highlights, for the first time, the modulation of the Kv3.1 by alpha-KTx 15.1, which could be an interesting starting compound for developing therapeutic biomolecules against Kv3.1-associated diseases. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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Review

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11 pages, 2839 KiB

Open AccessReview

Centipede Venom: A Potential Source of Ion Channel Modulators

by Anna Luo, Aili Wang, Peter Muiruri Kamau, Ren Lai and Lei Luo

Int. J. Mol. Sci. 2022, 23(13), 7105; https://doi.org/10.3390/ijms23137105 - 26 Jun 2022

Cited by 4 | Viewed by 2094

Abstract

Centipedes are one of the most ancient and successful living venomous animals. They have evolved spooky venoms to deter predators or hunt prey, and are widely distributed throughout the world besides Antarctica. Neurotoxins are the most important virulence factor affecting the function of [...] Read more.

Centipedes are one of the most ancient and successful living venomous animals. They have evolved spooky venoms to deter predators or hunt prey, and are widely distributed throughout the world besides Antarctica. Neurotoxins are the most important virulence factor affecting the function of the nervous system. Ion channels and receptors expressed in the nervous system, including Na_V, K_V, Ca_V, and TRP families, are the major targets of peptide neurotoxins. Insight into the mechanism of neurotoxins acting on ion channels contributes to our understanding of the function of both channels and centipede venoms. Meanwhile, the novel structure and selective activities give them the enormous potential to be modified and exploited as research tools and biological drugs. Here, we review the centipede venom peptides that act on ion channels. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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17 pages, 327 KiB

Open AccessReview

Antiviral Effects of Animal Toxins: Is There a Way to Drugs?

by Yuri Utkin, Andrei Siniavin, Igor Kasheverov and Victor Tsetlin

Int. J. Mol. Sci. 2022, 23(7), 3634; https://doi.org/10.3390/ijms23073634 - 26 Mar 2022

Cited by 11 | Viewed by 2246

Abstract

Viruses infect all types of organisms, causing viral diseases, which are very common in humans. Since viruses use the metabolic pathways of their host cells to replicate, they are difficult to eradicate without affecting the cells. The most effective measures against viral infections [...] Read more.

Viruses infect all types of organisms, causing viral diseases, which are very common in humans. Since viruses use the metabolic pathways of their host cells to replicate, they are difficult to eradicate without affecting the cells. The most effective measures against viral infections are vaccinations and antiviral drugs, which selectively inhibit the viral replication cycle. Both methods have disadvantages, which requires the development of new approaches to the treatment of viral diseases. In the study of animal venoms, it was found that, in addition to toxicity, venoms exhibit other types of biological activity, including an antiviral one, the first mention of which dates back to middle of the last century, but detailed studies of their antiviral activity have been conducted over the past 15 years. The COVID-19 pandemic has reinforced these studies and several compounds with antiviral activity have been identified in venoms. Some of them are very active and can be considered as the basis for antiviral drugs. This review discusses recent antiviral studies, the found compounds with high antiviral activity, and the possible mechanisms of their action. The prospects for using the animal venom components to create antiviral drugs, and the expected problems and possible solutions are also considered. Full article

(This article belongs to the Special Issue Venoms and Ion Channels 2.0)

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