CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

Teichert, Russell W.; Olivera, Baldomero M.; McIntosh, J. Michael; Bułaj, Grzegorz; Horvath, Martin P.

doi:10.1039/9781849737876-00163

Cited by 9 publications

(15 citation statements)

References 78 publications

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“…The conopeptide and the crassipeptide elicited the same types of effects in neurons that were affected by both. These effects are consistent with a variety of other K-channel blockers we have tested previously by the same method (Teichert et al, 2014a; Teichert et al, 2014b; Teichert et al, 2012a; Teichert et al, 2012b). …”

Section: Resultssupporting

confidence: 89%

“…The synthetic crassipeptides (cce9a, cce9b and iqi9a) were tested for biological activity using the Constellation Pharmacology platform that was previously described (Teichert et al, 2014a; Teichert et al, 2014b; Teichert et al, 2012a; Teichert et al, 2012b). All three peptides caused excitatory effects in a subset of cultured lumbar dorsal root ganglion (DRG) neurons.…”

Section: Resultsmentioning

confidence: 99%

“…The content of these high content assays is coupled to our on-going work to identify neuronal cell types and the cell-specific combinations of receptors and ion channels that they express (Smith et al, 2013; Teichert et al, 2014a; Teichert et al, 2014b; Teichert et al, 2012a; Teichert et al, 2012b). We refer to such cell-specific combinations of receptors and ion channels as “constellations” and therefore the pharmacological approach to elucidate these cell-specific constellations as “constellation pharmacology”.…”

Section: Discussionmentioning

confidence: 99%

“…We also have utilized both conventional electrophysiology, as well as constellation pharmacology, a new approach for elucidating the biological activity of such families of venom peptides. In this study, we show that by simultaneously assaying a broad spectrum of receptors and ion channels expressed in a heterogeneous mixture of different cell types (Smith et al, 2013; Teichert et al, 2014a; Teichert et al, 2014b; Teichert et al, 2012a; Teichert et al, 2012b), we are able to assess bioactivity and provide an initial definition of the potential selectivity of newly-discovered venom peptides.…”

Section: Introductionmentioning

confidence: 99%

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A family of excitatory peptide toxins from venomous crassispirine snails: Using Constellation Pharmacology to assess bioactivity

Imperial¹,

Cabang²,

Song³

et al. 2014

Toxicon

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The toxinology of the crassispirine snails, a major group of venomous marine gastropods within the superfamily Conoidea, is largely unknown. Here we define the first venom peptide superfamily, the P-like crassipeptides, and show that the organization of their gene sequences is similar to conotoxin precursors. We provide evidence that one peptide family within the P-like crassipeptide superfamily includes potassium-channel (K-channel) blockers, the κP-crassipeptides. Three of these peptides were chemically synthesized (cce9a, cce9b and iqi9a). Using conventional electrophysiology, cce9b was shown to be an antagonist of both a human KV1.1 channel isoform (Shaker subfamily of voltage-gated K channels) and a Drosophila K-channel isoform. We assessed the bioactivity of these peptides in native mammalian dorsal root ganglion neurons in culture. We demonstrate that two of these crassipeptides, cce9a and cce9b, elicited an excitatory phenotype in a subset of small-diameter capsaicin-sensitive mouse DRG neurons that were also affected by κJ-conotoxin pl14a, a blocker of KV1.6 channels. Given the vast potential complexity of heteromeric K-channel isoforms, this study demonstrates that the crassispirine venoms are a potentially rich source for discovering novel peptides that can help to identify and characterize the diversity of K-channel subtypes expressed in native neurons and other cell types.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A family of excitatory peptide toxins from venomous crassispirine snails: Using Constellation Pharmacology to assess bioactivity

Imperial¹,

Cabang²,

Song³

et al. 2014

Toxicon

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“…Bioactive components of C. tessulatus venom were screened using calcium imaging of native dorsal root ganglion (DRG) neurons (24)(25)(26)(27)(28). This enables the simultaneous evaluation of multiple biological activities of various venom components across a population of heterogeneous cell types.…”

Section: Significancementioning

confidence: 99%

Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus

Aman

Imperial

Ueberheide

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Prey shifts in carnivorous predators are events that can initiate the accelerated generation of new biodiversity. However, it is seldom possible to reconstruct how the change in prey preference occurred. Here we describe an evolutionary "smoking gun" that illuminates the transition from worm hunting to fish hunting among marine cone snails, resulting in the adaptive radiation of fish-hunting lineages comprising ∼100 piscivorous Conus species. This smoking gun is δ-conotoxin TsVIA, a peptide from the venom of Conus tessulatus that delays inactivation of vertebrate voltage-gated sodium channels. C. tessulatus is a species in a worm-hunting clade, which is phylogenetically closely related to the fish-hunting cone snail specialists. The discovery of a δ-conotoxin that potently acts on vertebrate sodium channels in the venom of a worm-hunting cone snail suggests that a closely related ancestral toxin enabled the transition from worm hunting to fish hunting, as δ-conotoxins are highly conserved among fish hunters and critical to their mechanism of prey capture; this peptide, δ-conotoxin TsVIA, has striking sequence similarity to these δ-conotoxins from piscivorous cone snail venoms. Calcium-imaging studies on dissociated dorsal root ganglion (DRG) neurons revealed the peptide's putative molecular target (voltagegated sodium channels) and mechanism of action (inhibition of channel inactivation). The results were confirmed by electrophysiology. This work demonstrates how elucidating the specific interactions between toxins and receptors from phylogenetically well-defined lineages can uncover molecular mechanisms that underlie significant evolutionary transitions.evolution | prey preference | cone snails | conotoxin

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Venom-derived modulators of epilepsy-related ion channels

Chow

Absalom

Biggs

et al. 2020

Biochemical Pharmacology

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Epilepsy is characterised by spontaneous recurrent seizures that are caused by an imbalance between neuronal excitability and inhibition. Since ion channels play fundamental roles in the generation and propagation of action potentials as well as neurotransmitter release at a subset of excitatory and inhibitory synapses, their dysfunction has been linked to a wide variety of epilepsies. Indeed, these unique proteins are the major biological targets for antiepileptic drugs. Selective targeting of a specific ion channel subtype remains challenging for small molecules, due to the high level of homology among members of the same channel family. As a consequence, there is a growing trend to target ion channels with biologics. Venoms are the best known natural source of ion channel modulators, and venom peptides are increasingly recognised as potential therapeutics due to their high selectivity and potency gained through millions of years of evolutionary selection pressure. Here we describe the major ion channel families involved in the pathogenesis of various types of epilepsy, including voltage-gated Na + , K + , Ca 2+ channels, Cys-loop receptors, ionototropic glutamate receptors and P2X receptors, and currently available venom-derived peptides that target these channel proteins. Although only a small number of venom peptides have successfully progressed to the clinic, there is reason to be optimistic about their development as anti-epileptic drugs, notwithstanding the challenges associated with development of any class of peptide drug.

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CHAPTER 6. The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

Cited by 9 publications

References 78 publications

A family of excitatory peptide toxins from venomous crassispirine snails: Using Constellation Pharmacology to assess bioactivity

A family of excitatory peptide toxins from venomous crassispirine snails: Using Constellation Pharmacology to assess bioactivity

Insights into the origins of fish hunting in venomous cone snails from studies of Conus tessulatus

Venom-derived modulators of epilepsy-related ion channels

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