Cone Snails: A Big Store of Conotoxins for Novel Drug Discovery

Gao, Bingmiao; Peng, Chao; Yang, Jiaan; Yi, Yunhai; Zhang, Junqing; Shi, Qiong

doi:10.3390/toxins9120397

Cited by 104 publications

(118 citation statements)

References 84 publications

(127 reference statements)

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“…While advancements in genomics, proteomics, and transcriptomics have rapidly accelerated the discovery of conotoxin peptides, the structural and pharmacological characterization has been rate-limiting. Notably, the ω-conotoxin MVIIA (Prialt®(ziconotide)), a non-opioid drug for intractable pain, remains the only FDA-approved conotoxin-based drug to date [14,15]. The majority of bioactive wealth from cone snail venoms awaits to be characterized.…”

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confidence: 99%

“…The majority of bioactive wealth from cone snail venoms awaits to be characterized. The classification and therapeutic applications of conotoxins have been reviewed in considerable detail [7,8,10,12,[14][15][16][17][18][19][20].Among the smallest of the peptides found in Conus venoms are the α-conotoxins, which competitively inhibit nicotinic acetylcholine receptors (nAChRs) [16]. α-conotoxins are typically 13-20 amino acids in length and disulfide-constrained.…”

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confidence: 99%

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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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RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats

et al. 2019

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“…Technological developments, particularly in the field of 'omics', have greatly facilitated our knowledge of how organisms (e.g., cone snails, snakes, spiders) produce toxins and how these components have evolved [22][23][24]. Transcriptomics and proteomics (see Glossary) have also enabled the sensitive detection and identification of toxins, including those that exhibit unique/specific biological properties.…”

Section: Technological Enablers For Toxinologymentioning

confidence: 99%

“…Transcriptomics and proteomics (see Glossary) have also enabled the sensitive detection and identification of toxins, including those that exhibit unique/specific biological properties. These high-throughput omic approaches have been successfully used as mining tools to identify around 2000 nucleotide and 8000 protein unique sequences from within cone snail venoms alone [24]; the vast majority are yet to be fully characterised for their structural or physiological properties. Current enabling technologies span the molecular, proteomic, chemical, biochemical, and structural fields.…”

Section: Technological Enablers For Toxinologymentioning

confidence: 99%

Friends or Foes? Emerging Impacts of Biological Toxins

Clark

Casewell

Elliott

et al. 2019

Trends in Biochemical Sciences

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Toxins are substances produced from biological sources (e.g., animal, plants, microorganisms) that have deleterious effects on a living organism. Despite the obvious health concerns of being exposed to toxins, they are having substantial positive impacts in a number of industrial sectors. Several toxin-derived products are approved for clinical, veterinary, or agrochemical uses. This review sets out the case for toxins as 'friends' that are providing the basis of novel medicines, insecticides, and even nucleic acid sequencing technologies. We also discuss emerging toxins ('foes') that are becoming increasingly prevalent in a range of contexts through climate change and the globalisation of food supply chains and that ultimately pose a risk to health. Toxins and Toxinology In the natural world, toxins are employed for diverse purposes, from the prey-incapacitating molecules found in snake, spider, and cone snail venom, to the defensive compounds harboured by numerous poisonous plant and animal species. While the consequences of human intoxication can be severe (Box 1), the functional diversity of biological toxins has led to their frequent use as experimental tools for studying physiological and pharmacological mechanisms (e.g., synaptic transmission, ion channel subtypes) (Figure 1). Toxinology involves the identification, characterisation, production, and engineering of biological toxins along with their application or repurposing as research tools and clinical products. As such, toxinology encompasses the study of the evolution, chemistry, biology, and clinical effects of toxins and includes potential biotechnological and/or therapeutic applications. Experimental applications of toxins as tools for physiologists go back a long time, including Claude Bernard's experiments in the 1800s with curare to demonstrate the existence of chemical signalling between nerves and muscles [2], and Henry Dale's use of muscarine and nicotine to show different subtypes of receptors for acetylcholine [3]. Snake toxins were critical for the first isolation of a receptor for a neurotransmitter [a-bungarotoxin and nicotinic acetylcholine receptors (nAChRs)] [4]. Recently, peptide toxins have been very useful in teasing out the functional importance of different subtypes of ion channels that are critical for neuronal function and cellular signalling [5-7]. An increasing number of toxins are now transitioning from the laboratory to the clinic and the balance of research in this aspect of toxinology is shifting from the classical development of anti-toxins and anti-venoms towards drug discovery [8,9]. The attraction of toxins for drug discovery lies in their often unique selectivity of their biological effects coupled with high potency. Toxic plant alkaloids were the first source of toxin-derived therapeutics, notably

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“…C. consors is a member of the Conoidea superfamily that consists of more than 700 species worldwide (Puillandre et al, 2014; Lavergne et al, 2015; Gao et al, 2017). C. consors lives in the tropical waters of the Indo-Pacific, inhabits sub-tidal coastlines, but is also found at depths of up to 200 meters, where it buries itself under sand and silt for shelter (http://biology.burke.washington.edu/conus/).…”

Section: Introductionmentioning

confidence: 99%