Venom Peptide

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Axel Touchard - One of the best experts on this subject based on the ideXlab platform.

  • Venom Peptide repertoire of the european myrmicine ant manica rubida: identification of insecticidal toxins
    Journal of Proteome Research, 2020
    Co-Authors: Axel Touchard, Samira R. Aili, Mrinalini, R. Manjunatha Kini, Alain Dejean, Nathan Téné, Valentine Barasse, Christophe Klopp, Laurent Coquet, Thierry Jouenne
    Abstract:

    Using an integrated transcriptomic and proteomic approach, we characterized the Venom peptidome of the European red ant, Manica rubida. We identified 13 "myrmicitoxins" that share sequence similarities with previously identified ant Venom Peptides, one of them being identified as an EGF-like toxin likely resulting from a threonine residue modified by O-fucosylation. Furthermore, we conducted insecticidal assays of reversed-phase HPLC Venom fractions on the blowfly Lucilia caesar, permitting us to identify six myrmicitoxins (i.e., U3-, U10-, U13-, U20-MYRTX-Mri1a, U10-MYRTX-Mri1b, and U10-MYRTX-Mri1c) with an insecticidal activity. Chemically synthesized U10-MYRTX-Mri1a, -Mri1b, -Mri1c, and U20-MYRTX-Mri1a irreversibly paralyzed blowflies at the highest doses tested (30-125 nmol·g-1). U13-MYRTX-Mri1a, the most potent neurotoxic Peptide at 1 h, had reversible effects after 24 h (150 nmol·g-1). Finally, U3-MYRTX-Mri1a has no insecticidal activity, even at up to 55 nmol·g-1. Thus, M. rubida employs a paralytic Venom rich in linear insecticidal Peptides, which likely act by disrupting cell membranes.

  • anti helicobacter pylori properties of the ant Venom Peptide bicarinalin
    Toxins, 2017
    Co-Authors: Jesus Guzman, Axel Touchard, Michel Treilhou, Nathan Téné, Denis Castillo, Haouaria Belkhelfa, Laila Haddiouihbabi, Michel Sauvain
    Abstract:

    The Venom Peptide bicarinalin, previously isolated from the ant Tetramorium bicarinatum, is an antimicrobial agent with a broad spectrum of activity. In this study, we investigate the potential of bicarinalin as a novel agent against Helicobacter pylori, which causes several gastric diseases. First, the effects of synthetic bicarinalin have been tested against Helicobacter pylori: one ATCC strain, and forty-four isolated from stomach ulcer biopsies of Peruvian patients. Then the cytoxicity of bicarinalin on human gastric cells and murine peritoneal macrophages was measured using XTT and MTT assays, respectively. Finally, the preventive effect of bicarinalin was evaluated by scanning electron microscopy using an adherence assay of H. pylori on human gastric cells treated with bicarinalin. This Peptide has a potent antibacterial activity at the same magnitude as four antibiotics currently used in therapies against H. pylori. Bicarinalin also inhibited adherence of H. pylori to gastric cells with an IC50 of 0.12 μg·mL−1 and had low toxicity for human cells. Scanning electron microscopy confirmed that bicarinalin can significantly decrease the density of H. pylori on gastric cells. We conclude that Bicarinalin is a promising compound for the development of a novel and effective anti-H. pylori agent for both curative and preventive use.

  • isolation and characterization of a structurally unique β hairpin Venom Peptide from the predatory ant anochetus emarginatus
    Biochimica et Biophysica Acta, 2016
    Co-Authors: Axel Touchard, Volker Herzig, Yanni K Y Chin, Ai-hua Jin, Alain Dejean, Andreas Brust, Fernanda Caldas Cardoso, Paul F. Alewood
    Abstract:

    Abstract Background Most ant Venoms consist predominantly of small linear Peptides, although some contain disulfide-linked Peptides as minor components. However, in striking contrast to other ant species, some Anochetus Venoms are composed primarily of disulfide-rich Peptides. In this study, we investigated the Venom of the ant Anochetus emarginatus with the aim of exploring these novel disulfide-rich Peptides. Methods The Venom peptidome was initially investigated using a combination of reversed-phase HPLC and mass spectrometry, then the amino acid sequences of the major Peptides were determined using a combination of Edman degradation and de novo MS/MS sequencing. We focused on one of these Peptides, U1-PONTX-Ae1a (Ae1a), because of its novel sequence, which we predicted would form a novel 3D fold. Ae1a was chemically synthesized using Fmoc chemistry and its 3D structure was elucidated using NMR spectroscopy. The Peptide was then tested for insecticidal activity and its effect on a range of human ion channels. Results Seven Peptides named poneritoxins (PONTXs) were isolated and sequenced. The three-dimensional structure of synthetic Ae1a revealed a novel, compact scaffold in which a C-terminal β-hairpin is connected to the N-terminal region via two disulfide bonds. Synthetic Ae1a reversibly paralyzed blowflies and inhibited human L-type voltage-gated calcium channels (CaV1). Conclusions Poneritoxins from Anochetus emarginatus Venom are a novel class of toxins that are structurally unique among animal Venoms. General significance This study demonstrates that Anochetus ant Venoms are a rich source of novel ion channel modulating Peptides, some of which might be useful leads for the development of biopesticides.

  • Isolation and characterization of a structurally unique β-hairpin Venom Peptide from the predatory ant Anochetus emarginatus
    Biochimica et Biophysica Acta (BBA) - General Subjects, 2016
    Co-Authors: Axel Touchard, Glenn F. King, Volker Herzig, Yanni K Y Chin, Ai-hua Jin, Alain Dejean, Andreas Brust, Fernanda Caldas Cardoso, Paul F. Alewood, Jérôme Orivel
    Abstract:

    Background: Most ant Venoms consist predominantly of small linear Peptides, although some contain disulfide linked Peptides as minor components. However, in striking contrast to other ant species, some Anochetus Venoms are composed primarily of disulfide-rich Peptides. In this study, we investigated the Venom of the ant Anochetus emarginatus with the aim of exploring these novel disulfide-rich Peptides. Methods: The Venom peptidome was initially investigated using a combination of reversed-phase HPLC and mass spectrometry, then the amino acid sequences of the major Peptides were determined using a combination of Edman degradation and de novo MS/MS sequencing. We focused on one of these Peptides, U-1-PONTX-Ae1a (Ae1a), because of its novel sequence, which we predicted would form a novel 3D fold. Ae1a was chemically synthesized using Fmoc chemistry and its 3D structure was elucidated using NMR spectroscopy. The Peptide was then tested for insecticidal activity and its effect on a range of human ion channels. Results: Seven Peptides named poneritoxins (PONTXs) were isolated and sequenced. The three-dimensional structure of synthetic Ae1a revealed a novel, compact scaffold in which a C-terminal beta-hairpin is connected to the N-terminal region via two disulfide bonds. Synthetic Ae1a reversibly paralyzed blowflies and inhibited human L-type voltage-gated calcium channels (Ca(v)1). Conclusions: Poneritoxins from Anochetus emarginatus Venom are a novel class of toxins that are structurally unique among animal Venoms. General significance: This study demonstrates that Anochetus ant Venoms are a rich source of novel ion channel modulating Peptides, some of which might be useful leads for the development of biopesticides.

  • diversity of Peptide toxins from stinging ant Venoms
    Toxicon, 2014
    Co-Authors: Samira R. Aili, Axel Touchard, Pierre Escoubas, Jérôme Orivel, Alain Dejean, Matthew P Padula, Graham M. Nicholson
    Abstract:

    Ants (Hymenoptera: Formicidae) represent a taxonomically diverse group of arthropods comprising nearly 13,000 extant species. Sixteen ant subfamilies have individuals that possess a stinger and use their Venom for purposes such as a defence against predators, competitors and microbial pathogens, for predation, as well as for social communication. They exhibit a range of activities including antimicrobial, haemolytic, cytolytic, paralytic, insecticidal and pain-producing pharmacologies. While ant Venoms are known to be rich in alkaloids and hydrocarbons, ant Venoms rich in Peptides are becoming more common, yet remain understudied. Recent advances in mass spectrometry techniques have begun to reveal the true complexity of ant Venom Peptide composition. In the few Venoms explored thus far, most Peptide toxins appear to occur as small polycationic linear toxins, with antibacterial properties and insecticidal activity. Unlike other Venomous animals, a number of ant Venoms also contain a range of homodimeric and heterodimeric Peptides with one or two interchain disulfide bonds possessing pore-forming, allergenic and paralytic actions. However, ant Venoms seem to have only a small number of monomeric disulfide-linked Peptides. The present review details the structure and pharmacology of known ant Venom Peptide toxins and their potential as a source of novel bioinsecticides and therapeutic agents.

Alain Dejean - One of the best experts on this subject based on the ideXlab platform.

  • Venom Peptide repertoire of the european myrmicine ant manica rubida: identification of insecticidal toxins
    Journal of Proteome Research, 2020
    Co-Authors: Axel Touchard, Samira R. Aili, Mrinalini, R. Manjunatha Kini, Alain Dejean, Nathan Téné, Valentine Barasse, Christophe Klopp, Laurent Coquet, Thierry Jouenne
    Abstract:

    Using an integrated transcriptomic and proteomic approach, we characterized the Venom peptidome of the European red ant, Manica rubida. We identified 13 "myrmicitoxins" that share sequence similarities with previously identified ant Venom Peptides, one of them being identified as an EGF-like toxin likely resulting from a threonine residue modified by O-fucosylation. Furthermore, we conducted insecticidal assays of reversed-phase HPLC Venom fractions on the blowfly Lucilia caesar, permitting us to identify six myrmicitoxins (i.e., U3-, U10-, U13-, U20-MYRTX-Mri1a, U10-MYRTX-Mri1b, and U10-MYRTX-Mri1c) with an insecticidal activity. Chemically synthesized U10-MYRTX-Mri1a, -Mri1b, -Mri1c, and U20-MYRTX-Mri1a irreversibly paralyzed blowflies at the highest doses tested (30-125 nmol·g-1). U13-MYRTX-Mri1a, the most potent neurotoxic Peptide at 1 h, had reversible effects after 24 h (150 nmol·g-1). Finally, U3-MYRTX-Mri1a has no insecticidal activity, even at up to 55 nmol·g-1. Thus, M. rubida employs a paralytic Venom rich in linear insecticidal Peptides, which likely act by disrupting cell membranes.

  • isolation and characterization of a structurally unique β hairpin Venom Peptide from the predatory ant anochetus emarginatus
    Biochimica et Biophysica Acta, 2016
    Co-Authors: Axel Touchard, Volker Herzig, Yanni K Y Chin, Ai-hua Jin, Alain Dejean, Andreas Brust, Fernanda Caldas Cardoso, Paul F. Alewood
    Abstract:

    Abstract Background Most ant Venoms consist predominantly of small linear Peptides, although some contain disulfide-linked Peptides as minor components. However, in striking contrast to other ant species, some Anochetus Venoms are composed primarily of disulfide-rich Peptides. In this study, we investigated the Venom of the ant Anochetus emarginatus with the aim of exploring these novel disulfide-rich Peptides. Methods The Venom peptidome was initially investigated using a combination of reversed-phase HPLC and mass spectrometry, then the amino acid sequences of the major Peptides were determined using a combination of Edman degradation and de novo MS/MS sequencing. We focused on one of these Peptides, U1-PONTX-Ae1a (Ae1a), because of its novel sequence, which we predicted would form a novel 3D fold. Ae1a was chemically synthesized using Fmoc chemistry and its 3D structure was elucidated using NMR spectroscopy. The Peptide was then tested for insecticidal activity and its effect on a range of human ion channels. Results Seven Peptides named poneritoxins (PONTXs) were isolated and sequenced. The three-dimensional structure of synthetic Ae1a revealed a novel, compact scaffold in which a C-terminal β-hairpin is connected to the N-terminal region via two disulfide bonds. Synthetic Ae1a reversibly paralyzed blowflies and inhibited human L-type voltage-gated calcium channels (CaV1). Conclusions Poneritoxins from Anochetus emarginatus Venom are a novel class of toxins that are structurally unique among animal Venoms. General significance This study demonstrates that Anochetus ant Venoms are a rich source of novel ion channel modulating Peptides, some of which might be useful leads for the development of biopesticides.

  • Isolation and characterization of a structurally unique β-hairpin Venom Peptide from the predatory ant Anochetus emarginatus
    Biochimica et Biophysica Acta (BBA) - General Subjects, 2016
    Co-Authors: Axel Touchard, Glenn F. King, Volker Herzig, Yanni K Y Chin, Ai-hua Jin, Alain Dejean, Andreas Brust, Fernanda Caldas Cardoso, Paul F. Alewood, Jérôme Orivel
    Abstract:

    Background: Most ant Venoms consist predominantly of small linear Peptides, although some contain disulfide linked Peptides as minor components. However, in striking contrast to other ant species, some Anochetus Venoms are composed primarily of disulfide-rich Peptides. In this study, we investigated the Venom of the ant Anochetus emarginatus with the aim of exploring these novel disulfide-rich Peptides. Methods: The Venom peptidome was initially investigated using a combination of reversed-phase HPLC and mass spectrometry, then the amino acid sequences of the major Peptides were determined using a combination of Edman degradation and de novo MS/MS sequencing. We focused on one of these Peptides, U-1-PONTX-Ae1a (Ae1a), because of its novel sequence, which we predicted would form a novel 3D fold. Ae1a was chemically synthesized using Fmoc chemistry and its 3D structure was elucidated using NMR spectroscopy. The Peptide was then tested for insecticidal activity and its effect on a range of human ion channels. Results: Seven Peptides named poneritoxins (PONTXs) were isolated and sequenced. The three-dimensional structure of synthetic Ae1a revealed a novel, compact scaffold in which a C-terminal beta-hairpin is connected to the N-terminal region via two disulfide bonds. Synthetic Ae1a reversibly paralyzed blowflies and inhibited human L-type voltage-gated calcium channels (Ca(v)1). Conclusions: Poneritoxins from Anochetus emarginatus Venom are a novel class of toxins that are structurally unique among animal Venoms. General significance: This study demonstrates that Anochetus ant Venoms are a rich source of novel ion channel modulating Peptides, some of which might be useful leads for the development of biopesticides.

  • diversity of Peptide toxins from stinging ant Venoms
    Toxicon, 2014
    Co-Authors: Samira R. Aili, Axel Touchard, Pierre Escoubas, Jérôme Orivel, Alain Dejean, Matthew P Padula, Graham M. Nicholson
    Abstract:

    Ants (Hymenoptera: Formicidae) represent a taxonomically diverse group of arthropods comprising nearly 13,000 extant species. Sixteen ant subfamilies have individuals that possess a stinger and use their Venom for purposes such as a defence against predators, competitors and microbial pathogens, for predation, as well as for social communication. They exhibit a range of activities including antimicrobial, haemolytic, cytolytic, paralytic, insecticidal and pain-producing pharmacologies. While ant Venoms are known to be rich in alkaloids and hydrocarbons, ant Venoms rich in Peptides are becoming more common, yet remain understudied. Recent advances in mass spectrometry techniques have begun to reveal the true complexity of ant Venom Peptide composition. In the few Venoms explored thus far, most Peptide toxins appear to occur as small polycationic linear toxins, with antibacterial properties and insecticidal activity. Unlike other Venomous animals, a number of ant Venoms also contain a range of homodimeric and heterodimeric Peptides with one or two interchain disulfide bonds possessing pore-forming, allergenic and paralytic actions. However, ant Venoms seem to have only a small number of monomeric disulfide-linked Peptides. The present review details the structure and pharmacology of known ant Venom Peptide toxins and their potential as a source of novel bioinsecticides and therapeutic agents.

Irina Vetter - One of the best experts on this subject based on the ideXlab platform.

  • Addition of K22 Converts Spider Venom Peptide Pme2a from an Activator to an Inhibitor of NaV1.7
    Biomedicines, 2020
    Co-Authors: Kathleen Yin, Glenn F. King, Volker Herzig, Jennifer R Deuis, Zoltan Dekan, Ai-hua Jin, Irina Vetter
    Abstract:

    Spider Venom is a novel source of disulfide-rich Peptides with potent and selective activity at voltage-gated sodium channels (NaV). Here, we describe the discovery of μ-theraphotoxin-Pme1a and μ/δ-theraphotoxin-Pme2a, two novel Peptides from the Venom of the Gooty Ornamental tarantula Poecilotheria metallica that modulate NaV channels. Pme1a is a 35 residue Peptide that inhibits NaV1.7 peak current (IC50 334 ± 114 nM) and shifts the voltage dependence of activation to more depolarised membrane potentials (V1/2 activation: Δ = +11.6 mV). Pme2a is a 33 residue Peptide that delays fast inactivation and inhibits NaV1.7 peak current (EC50 > 10 μM). Synthesis of a [+22K]Pme2a analogue increased potency at NaV1.7 (IC50 5.6 ± 1.1 μM) and removed the effect of the native Peptide on fast inactivation, indicating that a lysine at position 22 (Pme2a numbering) is important for inhibitory activity. Results from this study may be used to guide the rational design of spider Venom-derived Peptides with improved potency and selectivity at NaV channels in the future.

  • a centipede toxin family defines an ancient class of csαβ defensins
    Structure, 2019
    Co-Authors: Thomas S Dash, Jennifer R Deuis, Irina Vetter, Thomas Shafee, Peta J Harvey, Chuchu Zhang, Steve Peigneur, Jan Tytgat, Marilyn A Anderson, David J Craik
    Abstract:

    Summary Disulfide-rich Peptides (DRPs) play diverse physiological roles and have emerged as attractive sources of pharmacological tools and drug leads. Here we describe the 3D structure of a centipede Venom Peptide, U-SLPTX15-Sm2a, whose family defines a unique class of one of the most widespread DRP folds known, the cystine-stabilized α/β fold (CSαβ). This class, which we have named the two-disulfide CSαβ fold (2ds-CSαβ), contains only two internal disulfide bonds as opposed to at least three in all other confirmed CSαβ Peptides, and constitutes one of the major neurotoxic Peptide families in centipede Venoms. We show the 2ds-CSαβ is widely distributed outside centipedes and is likely an ancient fold predating the split between prokaryotes and eukaryotes. Our results provide insights into the ancient evolutionary history of a widespread DRP fold and highlight the usefulness of 3D structures as evolutionary tools.

  • a comprehensive portrait of the Venom of the giant red bull ant myrmecia gulosa reveals a hyperdiverse hymenopteran toxin gene family
    Science Advances, 2018
    Co-Authors: Samuel D. Robinson, Glenn F. King, Irina Vetter, Alexander Mueller, Daniel Clayton, Hana Starobova, Brett Hamilton, Richard J Payne, Eivind A. B. Undheim
    Abstract:

    Ants (Hymenoptera: Formicidae) are diverse and ubiquitous, and their ability to sting is familiar to many of us. However, their Venoms remain largely unstudied. We provide the first comprehensive characterization of a polypeptidic ant Venom, that of the giant red bull ant, Myrmecia gulosa. We reveal a suite of novel Peptides with a range of posttranslational modifications, including disulfide bond formation, dimerization, and glycosylation. One Venom Peptide has sequence features consistent with an epidermal growth factor fold, while the remaining Peptides have features suggestive of a capacity to form amphipathic helices. We show that these Peptides are derived from what appears to be a single, pharmacologically diverse, gene superfamily (aculeatoxins) that includes most Venom Peptides previously reported from the aculeate Hymenoptera. Two aculeatoxins purified from the Venom were found to be capable of activating mammalian sensory neurons, consistent with the capacity to produce pain but via distinct mechanisms of action. Further investigation of the major Venom Peptide MIITX1-Mg1a revealed that it can also incapacitate arthropods, indicative of dual utility in both defense and predation. MIITX1-Mg1a accomplishes these functions by generating a leak in membrane ion conductance, which alters membrane potential and triggers neuronal depolarization. Our results provide the first insights into the evolution of the major toxin gene superfamily of the aculeate Hymenoptera and provide a new paradigm in the functional evolution of toxins from animal Venoms.

  • a centipede toxin family defines a new ancient class of csαβ defensins
    2018
    Co-Authors: Thomas S Dash, Jennifer R Deuis, Irina Vetter, Thomas Shafee, Peta J Harvey, Chuchu Zhang, Steve Peigneur, Jan Tytgat, Marilyn A Anderson, David J Craik
    Abstract:

    Disulfide rich Peptides (DRPs) play diverse physiological roles and have emerged as attractive sources of pharmacological tools and drug leads. Here we describe the 3D structure of a centipede Venom Peptide that defines a new class of one of the most widespread DRP folds known, the cystine-stabilised α/β fold (CSαβ). This new class, which we have named the two-disulfide CSαβ fold (2ds-CSαβ), contains only two internal disulfide bonds as opposed to at least three in all other confirmed CSαβ Peptides, and constitutes one of the major neurotoxic Peptide families in giant centipede Venoms. We show the 2ds-CSαβ is also widely distributed outside centipedes, and probably shares an evolutionary origin with all other CSαβ that predates the split between prokaryotes and eukaryotes. Our results highlight the usefulness of 3D structures as evolutionary tools and provides some of the first insights into the ancient evolutionary history of any DRP fold.

  • lethal effects of an insecticidal spider Venom Peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors
    Neuropharmacology, 2017
    Co-Authors: Monique J Windley, Richard J. Lewis, Irina Vetter, Graham M. Nicholson
    Abstract:

    Abstract κ-Hexatoxins (κ-HXTXs) are a family of excitotoxic insect-selective neurotoxins from Australian funnel-web spiders that are lethal to a wide range of insects, but display no toxicity towards vertebrates. The prototypic κ-HXTX-Hv1c selectively blocks native and expressed cockroach large-conductance calcium-activated potassium (BKCa or KCa1.1) channels, but not their mammalian orthologs. Despite this potent and selective action on insect KCa1.1 channels, we found that the classical KCa1.1 blockers paxilline, charybdotoxin and iberiotoxin, which all block insect KCa1.1 channels, are not lethal in crickets. We therefore used whole-cell patch-clamp analysis of cockroach dorsal unpaired median (DUM) neurons to study the effects of κ-HXTX-Hv1c on sodium-activated (KNa), delayed-rectifier (KDR) and ‘A-type’ transient (KA) K+ channels. 1 μM κ-HXTX-Hv1c failed to significantly inhibit cockroach KNa and KDR channels, but did cause a 30 ± 7% saturating inhibition of KA channel currents, possibly via a Kv4 (Shal-like) action. However, this modest action at such a high concentration of κ-HXTX-Hv1c would indicate a different lethal target. Accordingly, we assessed the actions of κ-HXTX-Hv1c on neurotransmitter-gated ion channels in cockroach DUM neurons. We found that κ-HXTX-Hv1c failed to produce any major effects on GABAA or glutamate-Cl receptors but dramatically slowed nicotine-evoked ACh receptor (nAChR) current decay and reversed nAChR desensitization. These actions occurred without any alterations to nAChR current amplitude or the nicotine concentration-response curve, and are consistent with a positive allosteric modulation of nAChRs. κ-HXTX-Hv1c therefore represents the first Venom Peptide that selectively modulates insect nAChRs with a mode of action similar to the excitotoxic insecticide spinosyn A. This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’

Glenn F. King - One of the best experts on this subject based on the ideXlab platform.

  • Venom composition of the endoparasitoid wasp cotesia flavipes hymenoptera braconidae and functional characterization of a major Venom Peptide
    Toxicon, 2021
    Co-Authors: Ciro Pedro Guidotti Pinto, Samuel D. Robinson, Glenn F. King, Yanni K Y Chin, Andrew A Walker, Guilherme Duarte Rossi
    Abstract:

    Endoparasitoid wasps use complex biochemical arsenals to suppress the normal humoral and cellular immune responses of their hosts in order to transform them into a suitable environment for development of their eggs and larvae. Venom injected during oviposition is a key component of this arsenal, but the functions of individual Venom toxins are still poorly understood. Furthermore, there has been little investigation of the potential biotechnological use of these Venom toxins, for example for control of agricultural pests. The endoparasitoid Cotesia flavipes (Hymenoptera: Braconidae) is a biocontrol agent reared in biofactories and released extensively in Brazil to control the sugarcane borer Diatraea saccharalis (Lepidoptera: Crambidae). The objectives of this work were to reveal Venom components produced by C. flavipes and explore the function of a major Venom Peptide, Cf4. Using a combined proteomic/transcriptomic approach, we identified 38 putative Venom toxins including both linear and disulfide-rich Peptides, hydrolases, protease inhibitors, apolipophorins, lipid-binding proteins, and proteins of the odorant binding families. Because of its high abundance in the Venom, we selected Cf4, a 33-residue Peptide with three disulfide bonds, for synthesis and further characterization. We found that synthetic Cf4 reduced the capacity of D. saccharalis hemocytes to encapsulate foreign bodies without any effect on phenoloxidase activity, consistent with a role in disruption of the cellular host immune response. Feeding leaves coated with Cf4 to neonate D. saccharalis resulted in increased mortality and significantly reduced feeding compared to caterpillars fed untreated leaves, indicating that Cf4 is a potential candidate for insect pest control through ingestion. This study adds to our knowledge of endoparasitoid wasp Venoms composition, host regulation mechanisms and their biotechnological potential for pest management.

  • Addition of K22 Converts Spider Venom Peptide Pme2a from an Activator to an Inhibitor of NaV1.7
    Biomedicines, 2020
    Co-Authors: Kathleen Yin, Glenn F. King, Volker Herzig, Jennifer R Deuis, Zoltan Dekan, Ai-hua Jin, Irina Vetter
    Abstract:

    Spider Venom is a novel source of disulfide-rich Peptides with potent and selective activity at voltage-gated sodium channels (NaV). Here, we describe the discovery of μ-theraphotoxin-Pme1a and μ/δ-theraphotoxin-Pme2a, two novel Peptides from the Venom of the Gooty Ornamental tarantula Poecilotheria metallica that modulate NaV channels. Pme1a is a 35 residue Peptide that inhibits NaV1.7 peak current (IC50 334 ± 114 nM) and shifts the voltage dependence of activation to more depolarised membrane potentials (V1/2 activation: Δ = +11.6 mV). Pme2a is a 33 residue Peptide that delays fast inactivation and inhibits NaV1.7 peak current (EC50 > 10 μM). Synthesis of a [+22K]Pme2a analogue increased potency at NaV1.7 (IC50 5.6 ± 1.1 μM) and removed the effect of the native Peptide on fast inactivation, indicating that a lysine at position 22 (Pme2a numbering) is important for inhibitory activity. Results from this study may be used to guide the rational design of spider Venom-derived Peptides with improved potency and selectivity at NaV channels in the future.

  • Can we resolve the taxonomic bias in spider Venom research?
    Elsevier, 2019
    Co-Authors: Volker Herzig, Glenn F. King, Eivind A. B. Undheim
    Abstract:

    The rate of discovery of new spider species greatly exceeds the rate of spider Venom characterisation, leading to an increasing number of species with unstudied Venoms. However, recent advances in proteomics and genomics that enable the study of Venoms from smaller species has expanded the accessible taxonomic range. Thus, although the number of unstudied spider Venoms is likely to further increase, future research should focus on the characterisation of Venoms and toxins from previously unstudied spider families. Keywords: Spider, Venom, Peptide, Diversity, Taxonomic, Transcriptomics, Proteomic

  • a comprehensive portrait of the Venom of the giant red bull ant myrmecia gulosa reveals a hyperdiverse hymenopteran toxin gene family
    Science Advances, 2018
    Co-Authors: Samuel D. Robinson, Glenn F. King, Irina Vetter, Alexander Mueller, Daniel Clayton, Hana Starobova, Brett Hamilton, Richard J Payne, Eivind A. B. Undheim
    Abstract:

    Ants (Hymenoptera: Formicidae) are diverse and ubiquitous, and their ability to sting is familiar to many of us. However, their Venoms remain largely unstudied. We provide the first comprehensive characterization of a polypeptidic ant Venom, that of the giant red bull ant, Myrmecia gulosa. We reveal a suite of novel Peptides with a range of posttranslational modifications, including disulfide bond formation, dimerization, and glycosylation. One Venom Peptide has sequence features consistent with an epidermal growth factor fold, while the remaining Peptides have features suggestive of a capacity to form amphipathic helices. We show that these Peptides are derived from what appears to be a single, pharmacologically diverse, gene superfamily (aculeatoxins) that includes most Venom Peptides previously reported from the aculeate Hymenoptera. Two aculeatoxins purified from the Venom were found to be capable of activating mammalian sensory neurons, consistent with the capacity to produce pain but via distinct mechanisms of action. Further investigation of the major Venom Peptide MIITX1-Mg1a revealed that it can also incapacitate arthropods, indicative of dual utility in both defense and predation. MIITX1-Mg1a accomplishes these functions by generating a leak in membrane ion conductance, which alters membrane potential and triggers neuronal depolarization. Our results provide the first insights into the evolution of the major toxin gene superfamily of the aculeate Hymenoptera and provide a new paradigm in the functional evolution of toxins from animal Venoms.

  • Venom Peptides as therapeutics: advances, challenges and the future of Venom-Peptide discovery
    Expert Review of Proteomics, 2017
    Co-Authors: Samuel D. Robinson, Eivind A. B. Undheim, Beatrix Ueberheide, Glenn F. King
    Abstract:

    ABSTRACTIntroduction: Animal Venoms are complex chemical arsenals. Most Venoms are rich in bioactive Peptides with proven potential as research tools, drug leads and drugs.Areas covered: We review recent advances in Venom-Peptide discovery, particularly the adoption of combined transcriptomic/proteomic approaches for the exploration of Venom composition.Expert commentary: Advances in transcriptomics and proteomics have dramatically altered the manner and rate of Venom-Peptide discovery. The increasing trend towards a toxin-driven approach, as opposed to traditional target-based screening of Venoms, is likely to expedite the discovery of Venom-Peptides with novel structures and new and unanticipated mechanisms of action. At the same time, these advances will drive the development of higher-throughput approaches for target identification. Taken together, these approaches should enhance our understanding of the natural ecological function of Venom Peptides and increase the rate of identification of novel ven...

Macdonald J. Christie - One of the best experts on this subject based on the ideXlab platform.

  • spider Venom Peptide pn3a inhibition of primary afferent high voltage activated calcium channels
    Frontiers in Pharmacology, 2021
    Co-Authors: Jeffrey R Mcarthur, Nehan R Munasinghe, Rocio K Finolurdaneta, David J Adams, Macdonald J. Christie
    Abstract:

    Despite potently inhibiting the nociceptive voltage-gated sodium (Nav) channel, Nav1.7, µ-theraphotoxin Pn3a is antinociceptive only upon co-administration with sub-therapeutic opioid agonists, or by itself at doses >3,000-fold greater than its Nav1.7 IC50 by a yet undefined mechanism. Nav channels are structurally related to voltage-gated calcium (Cav) channels, Cav1 and Cav2. These channels mediate the high voltage-activated (HVA) calcium currents (ICa ) that orchestrate synaptic transmission in nociceptive dorsal root ganglion (DRG) neurons and are fine-tuned by opioid receptor (OR) activity. Using whole-cell patch clamp recording, we found that Pn3a (10 µM) inhibits ∼55% of rat DRG neuron HVA-ICa and 60-80% of Cav1.2, Cav1.3, Cav2.1, and Cav2.2 mediated currents in HEK293 cells, with no inhibition of Cav2.3. As a major DRG ICa component, Cav2.2 inhibition by Pn3a (IC50 = 3.71 ± 0.21 µM) arises from an 18 mV hyperpolarizing shift in the voltage dependence of inactivation. We observed that co-application of Pn3a and µ-OR agonist DAMGO results in enhanced HVA-ICa inhibition in DRG neurons whereas co-application of Pn3a with the OR antagonist naloxone does not, underscoring HVA channels as shared targets of Pn3a and opioids. We provide evidence that Pn3a inhibits native and recombinant HVA Cavs at previously reportedly antinociceptive concentrations in animal pain models. We show additive modulation of DRG HVA-ICa by sequential application of low Pn3a doses and sub-therapeutic opioids ligands. We propose Pn3a's antinociceptive effects result, at least in part, from direct inhibition of HVA-ICa at high Pn3a doses, or through additive inhibition by low Pn3a and mild OR activation.

  • Conus Venom Peptide pharmacology.
    Pharmacological reviews, 2012
    Co-Authors: Richard J. Lewis, Sebastien Dutertre, Macdonald J. Christie
    Abstract:

    ConoPeptides are a diverse group of recently evolved Venom Peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conoPeptides, with those pharmacologically characterized (≈ 0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conoPeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conoPeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail Venom Peptide families acting at voltage-gated ion channels (ω-, μ-, μO-, δ-, ι-, and κ-conotoxins), ligand-gated ion channels (α-conotoxins, σ-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (ρ-conoPeptides, conopressins, and contulakins), and neurotransmitter transporters (χ-conoPeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conoPeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conoPeptides have had as both research probes and leads to new therapies.