Structural and Functional Analyses of Cone Snail Toxins

Duque, Harry Morales; Dias, Simoni Campos; Franco, Octávio Luiz

doi:10.3390/md17060370

Cited by 24 publications

(16 citation statements)

References 189 publications

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“…Conotoxins are typically 8-60 amino acid peptides that potently interact with a wide range of voltage-and ligand-gated ion channels and receptors [64]. The cone snail venom peptides evolved to capture their prey (worms, fish, and other mollusks), and their venom is known to interact and modulate several mammalian ion channels with great selectivity [65].…”

Section: Molluscan Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

“…Mature conotoxins are structurally diverse, including disulfide-free and mono-and poly-disulfidebonded peptides (several reviews deal with the structural diversity of conotoxins; see References [64,68]). Peptides lacking disulfide bonds are flexible, whereas the presence of multiple disulfide linkages provides structural rigidity and provides different three-dimensional conformations depending on the cysteine disulfide framework within the toxin sequence [69].…”

Section: Molluscan Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

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Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

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Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

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Section: Molluscan Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

Section: Molluscan Peptides That Inhibit Kv1 Channelsmentioning

confidence: 99%

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

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“…The conotoxin open reading frame (ORF) generally consists of a signal sequence named the pre region, an intervening pro region called sometimes the propeptide, the mature peptide region, and, sometimes, a region located after the mature peptide that is excised out during maturation [5][6][7][8][9]. These peptide toxins have been the subject of considerable attention, including their utility as molecular tools in the field of physiology, largely due to their high potency and specificity on human ion channels [10,11]. These same properties confer them potential for important clinical applications in their native form or as models for drug design.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Conotoxin Precursors from the Cone Snail Conus spurius by High-Throughput RNA Sequencing

et al. 2021

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Marine gastropods of the genus Conus, comprising more than 800 species, have the characteristic of injecting worms and other prey with venom. These conopeptide toxins, highly diverse in structure and action, are highly potent and specific for their molecular targets (ion channels, receptors, and transporters of the prey’s nervous system), and thus are important research tools and source for drug discovery. Next-generation sequencing technologies are speeding up the discovery of novel conopeptides in many of these species, but only limited information is available for Conus spurius, which inhabits sandy mud. To search for new precursor conopeptides, we analyzed the transcriptome of the venous ducts of C. spurius and identified 55 putative conotoxins. Seven were selected for further study and confirmed by Sanger sequencing to belong to the M-superfamily (Sr3.M01 and Sr3.M02), A-superfamily (Sr1.A01 and Sr1.A02), O-superfamily (Sr15.O01), and Con-ikot-ikot (Sr21.CII01 and Sr22.CII02). Six of these have never been reported. To our knowledge, this report is the first to use high-throughput RNA sequencing for the study of the diversity of C. spurius conotoxins.

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“…Typical conotoxins contain 10-30 amino acids with multiple disulfide bonds and post-translational modifications [ 3 , 4 ]. Due to the high specificity and selectivity of conotoxins in targeting ion channels and neurotransmitter receptors, conotoxins have become a research hotspot in the neuropharmacology field [ 5 ]. One of the calcium channel inhibitors, ω-conotoxin MVIIA (ziconotide), was proved by the United States Food and Drug Administration (FDA) in 2004 for treating intractable pain [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

A novel proline-rich M-superfamily conotoxin that can simultaneously affect sodium, potassium and calcium currents

Yang

Liu

et al. 2021

J. Venom. Anim. Toxins incl. Trop. Dis

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Background Conotoxins have become a research hotspot in the neuropharmacology field for their high activity and specificity in targeting ion channels and neurotransmitter receptors. There have been reports of a conotoxin acting on two ion channels, but rare reports of a conotoxin acting on three ion channels. Methods Vr3a, a proline-rich M-superfamily conotoxin from a worm-hunting Conus varius , was obtained by solid-phase synthesis and identified by mass spectrometry. The effects of synthesized Vr3a on sodium, potassium and calcium currents were tested on rat DRG cells by patch clamp experiments. The further effects of Vr3a on human Ca v 1.2 and Ca v 2.2 currents were tested on HEK293 cells. Results About 10 μM Vr3a has no effects on the peak sodium currents, but can induce a ~10 mV shift in a polarizing direction in the current-voltage relationship. In addition, 10 μM Vr3a can increase 19.61 ± 5.12% of the peak potassium currents and do not induce a shift in the current-voltage relationship. An amount of 10 μM Vr3a can inhibit 31.26% ± 4.53% of the peak calcium currents and do not induce a shift in the current-voltage relationship. The IC 50 value of Vr3a on calcium channel currents in rat DRG neurons is 19.28 ± 4.32 μM. Moreover, 10 μM Vr3a can inhibit 15.32% ± 5.41% of the human Ca v 1.2 currents and 12.86% ± 4.93% of the human Ca v 2.2 currents. Conclusions Vr3a can simultaneously affect sodium, potassium and calcium currents. This novel triple-target conotoxin Vr3a expands understanding of conotoxin functions.

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Structural and Functional Analyses of Cone Snail Toxins

Cited by 24 publications

References 189 publications

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Identification of Novel Conotoxin Precursors from the Cone Snail Conus spurius by High-Throughput RNA Sequencing

A novel proline-rich M-superfamily conotoxin that can simultaneously affect sodium, potassium and calcium currents

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