Conotoxins: Chemistry and Biology

Jin, Aihua; Muttenthaler, Markus; Dutertre, Sébastien; Himaya, S.W.A.; Kaas, Quentin; Craik, David J.; Lewis, Richard J.; Alewood, Paul F.

doi:10.1021/acs.chemrev.9b00207

Cited by 179 publications

(206 citation statements)

References 264 publications

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“…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%

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%

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

et al. 2020

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“…Previous estimates of 50-200 unique compounds per venom have been expanded nearly 10-fold with the advancement of mass spectroscopy and venomics techniques. These estimates yield a collection of greater than 1 million potential lead peptide compounds to be characterized, less than 1% of which (~10,000) have been partially characterized [12,13]. While advancements in genomics, proteomics, and transcriptomics have rapidly accelerated the discovery of conotoxin peptides, the structural and pharmacological characterization has been rate-limiting.…”

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confidence: 99%

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

et al. 2019

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Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of α9α10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.Patients have exhibited several types of neuropathies, including numbness, chronic pain, and allodynia (painful hypersensitivity) to mechanical or thermal stimuli [5]. Amongst patients, however, the type, duration, and severity of neuropathy can vary [6]. While the prevalence and manifestations of paclitaxel-induced neuropathy have been well documented, the underlying mechanisms are still being characterized. Several adjuvant treatments have been used in an attempt to combat the effects of chemotherapy-induced peripheral neuropathy (CIPN). However, there are currently no FDA-approved medications for the prevention or treatment of CIPN.Cone snails have historically displayed a repertoire of therapeutic molecules. The venomous marine gastropods of the genus Conus are a diverse collection of snails that have developed complex hunting and envenomation strategies. The venoms of these snails contain hundreds of unique peptides, and the contents of these venoms can also change in response to defensive or predatory stimuli [7]. Cone snails have refined a suite of bioactive peptides that can exquisitely and potently discriminate among receptors involved in neurotransmission. These targets include G-protein-coupled receptors and voltage-and ligand-gated ion channels [8]. The chemical arsenal of each snail also contains bioactive compounds that have been characterized as prey-endogenous mimetics, such as the insulin-like peptide used by Conus geographus, which more closely resembles fish insulin than its own [9]. The discovery of this molecular mimicry strategy spurred the characterization of several other hormone/neuropeptide-like peptides in the venom reperto...

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“…Conotoxins have huge pharmaceutical potential as shown by Prialt, a -conotoxin that has been FDA-approved as a drug to treat chronic pain. 62,63 With over 10,000 conotoxins identified, our platform may provide a powerful method for the production of conotoxins previously inaccessible by chemical synthesis or recombinant expression. In the past, several conotoxins were developed as intrathecal therapies but this approach lacks commercial or widespread clinical interest.…”

Section: Scale-up Production Of Cp In Bioreactors P Pastoris Expresmentioning

confidence: 99%

An environmentally sustainable biomimetic production of cyclic disulfide-rich peptides

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et al. 2020

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Conotoxins: Chemistry and Biology

Cited by 179 publications

References 264 publications

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

An environmentally sustainable biomimetic production of cyclic disulfide-rich peptides

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