Inhibition of cholinergic pathways in<i>Drosophila melanogaster</i>by α‐conotoxins

Heghinian, Mari D.; Mejia, Monica; Adams, David J.; Godenschwege, Tanja A.; Marí, Frank

doi:10.1096/fj.14-262733

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…This is consistent with the results in mice where gm9a induced hypersensitivity and excitability suggesting that DSC1 channels might be a target of these conotoxins, albeit not the only target. This is unlike the D α7 nAChR specific toxins, such as α‐conotoxins, which inhibit the DLM at picomolar quantities …”

Section: Discussionmentioning

confidence: 93%

Transforming conotoxins into cyclotides: Backbone cyclization of P‐superfamily conotoxins

et al. 2015

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Peptide backbone cyclization is a widely used approach to improve the activity and stability of small peptides but until recently it had not been applied to peptides with multiple disulfide bonds. Conotoxins are disulfide-rich conopeptides derived from the venoms of cone snails that have applications in drug design and development. However, because of their peptidic nature, they can suffer from poor bioavailability and poor stability in vivo. In this study two P-superfamily conotoxins, gm9a and bru9a, were backbone cyclized by joining the N- and C-termini with short peptide linkers using intramolecular native chemical ligation chemistry. The cyclized derivatives had conformations similar to the native peptides showing that backbone cyclization can be applied to three disulfide-bonded peptides with cystine knot motifs. Cyclic gm9a was more potent at high voltage-activated (HVA) calcium channels than its acyclic counterpart, highlighting the value of this approach in developing active and stable conotoxins containing cyclic cystine knot motifs.

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Section: Discussionmentioning

confidence: 93%

Transforming conotoxins into cyclotides: Backbone cyclization of P‐superfamily conotoxins

et al. 2015

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“…Conotoxins can be divided into different pharmacological families according to their molecular targets and gene superfamilies according to their precursor signal peptides, such as α‐, αA‐, αB‐, αC‐, αD‐, αO‐, αS‐, μ‐, ω‐, κ‐, δ‐, ψ‐, σ‐, ρ‐, and γ‐ . Conotoxins have been proved as effective potential therapeutic agents to treat various diseases including chronic pain, Parkinson's disease, Alzheimer's disease, cancer, and drug addiction . One example of a Conus ‐based peptide developed as an analgesic drug is ω‐conotoxin MVIIA (ziconotide), which has been approved by the U.S. Food and Drug Administration (FDA) .…”

Section: Introductionmentioning

confidence: 99%

Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO‐Conotoxin GeXIVA[1,2] and GeXIVA [1,4]

et al. 2018

Chem Biol Drug Des

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αO-conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation, and thiol, which would be the key factors to affect stabilities of the two isomers in vivo. Simultaneously, forced degradation was carried out to evaluate stabilities of the two isomers. GeXIVA[1,2] and GeXIVA[1,4] were unstable when they were incubated in serum and digestive enzymes at 37°C. Their disulfide bond frameworks were easy to be scrambled in GSH and HSA. For different stress conditions, their stabilities were impacted greatly by oxidation, temperature, and alkaline conditions. The results may provide a foundation for storage conditions, structural modification, and pharmaceutical preparation of GeXIVA[1,2] and GeXIVA[1,4].

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“…For instance, in a 2014 study Heghinian and co-workers used several different α-conotoxins to perform structurally guided mutations in the D. melanogaster α7 nAChR, allowing this receptor to display similar selectivity for various conotoxins as the mammalian counterpart. This, in turn, resulted in D. melanogaster cholinergic synapses that mimic the synaptic behavior of vertebrate synapses, improving the suitability of these mutant flies as a tool for in vivo drug discovery [61].…”

Section: Research Toolsmentioning

confidence: 99%

“…Lastly, conotoxins are among the most rapidly evolving gene products known in nature and have served as tools in a diverse range of studies on the effects of feeding ecology, prey taxa, dietary breadth, age and geographical heterogeneity on the evolution of venom genes [72][73][74][75][76], and studies on the role of gene duplication and positive selection on venom gene expression and diversification [77][78][79]. Elucidating peptide biosynthesis and folding [68][69][70] α-ImI α7 nAChR Subtype selectivity [56] Targeted drug delivery in cancer [62], engineering D. melanogaster as better human disease model [61], chromaffin cell signaling [57] α-MII nAChR Subtype selective [80] Inflammation [81], reward and addiction [82,83] α-Vc1.1 and α-Rg1A α9α10 nAChR Subtype selective [84,85] Neuropathic pain and inflammation [86][87][88], immunology [89][90][91] Con-ikot-ikot AMPA receptor…”

Section: Research Toolsmentioning

confidence: 99%

Curses or Cures: A Review of the Numerous Benefits Versus the Biosecurity Concerns of Conotoxin Research

et al. 2020

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Conotoxins form a diverse group of peptide toxins found in the venom of predatory marine cone snails. Decades of conotoxin research have provided numerous measurable scientific and societal benefits. These include their use as a drug, diagnostic agent, drug leads, and research tools in neuroscience, pharmacology, biochemistry, structural biology, and molecular evolution. Human envenomations by cone snails are rare but can be fatal. Death by envenomation is likely caused by a small set of toxins that induce muscle paralysis of the diaphragm, resulting in respiratory arrest. The potency of these toxins led to concerns regarding the potential development and use of conotoxins as biological weapons. To address this, various regulatory measures have been introduced that limit the use and access of conotoxins within the research community. Some of these regulations apply to all of the ≈200,000 conotoxins predicted to exist in nature of which less than 0.05% are estimated to have any significant toxicity in humans. In this review we provide an overview of the many benefits of conotoxin research, and contrast these to the perceived biosecurity concerns of conotoxins and research thereof.

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Inhibition of cholinergic pathways inDrosophila melanogasterby α‐conotoxins

Cited by 8 publications

References 37 publications

Transforming conotoxins into cyclotides: Backbone cyclization of P‐superfamily conotoxins

Transforming conotoxins into cyclotides: Backbone cyclization of P‐superfamily conotoxins

Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO‐Conotoxin GeXIVA[1,2] and GeXIVA [1,4]

Curses or Cures: A Review of the Numerous Benefits Versus the Biosecurity Concerns of Conotoxin Research

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