Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Toxins".

Deadline for manuscript submissions: closed (25 November 2023) | Viewed by 12478

Special Issue Editors


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Guest Editor
ARC Training Centre for Green Chemistry in Manufacturing, School of Chemistry, Monash University, Clayton, VIC 3800, Australia
Interests: peptide synthesis; bioactive peptides; disulphide mimetics; alkene and alkyne metathesis; green chemistry; sustainability

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Guest Editor
School of Chemistry, Monash University, Clayton, VIC 3800, Australia
Interests: organometallic synthesis; peptidomimetics; ALTMET polymerisation; natural products; renewables chemistry

Special Issue Information

Dear Colleagues,

The venom of marine cone snails contains a plethora of peptides with exquisite activity. These peptides, known as conotoxins, are short peptides with multiple disulphide bridges in a varied framework that constrains their structure. They also usually bear post-translational modifications such as the amidation of the C-terminus, the cyclisation of an N-terminal glutamine residue into pyroglutamic acid as well as hydroxylation, bromination, γ-carboxylation, and sulfation. Conotoxins interact with human ion channels, G-protein coupled receptors, and transporters in the nervous system which makes them appealing drug candidates.

Recent advances have been made in the understanding of the interactions between GABAB receptors and a-conotoxins. The mode of action of many other conotoxins is still elusive; however, a clear understanding is crucial for the design of analogues that are robust candidates in clinical trials and that can ultimately be developed as drugs.

This Special Issue invites contributions on the following topics: the identification and characterisation of novel conotoxins and synthesis of novel conotoxin analogues or small molecule mimetics with an improved pharmacological profile that can contribute to the understanding of the mechanism of action.

Dr. Alessia Belgi
Prof. Dr. Andrea Jane Robinson
Guest Editors

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Keywords

  • conotoxin
  • conotoxin analogue
  • novel conotoxin
  • conotoxin mimetic
  • mode of action

Published Papers (7 papers)

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Research

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16 pages, 3103 KiB  
Article
αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model
by Huanbai Wang, Xiaodan Li, Yamin Qiao, Meiting Wang, Wen Wang, J. Michael McIntosh, Dongting Zhangsun and Sulan Luo
Mar. Drugs 2024, 22(1), 49; https://doi.org/10.3390/md22010049 - 19 Jan 2024
Cited by 2 | Viewed by 2032
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the [...] Read more.
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks had no effect on the mice’s normal pain threshold or locomotor activity and anxiety-like behavior, as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA sequencing results identified 209 differentially expressed genes (DEGs) in the CIPN model, and simultaneously injecting GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by the cytokine–cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin-induced CIPN management. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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11 pages, 651 KiB  
Article
Synthesis of Cystine-Stabilised Dicarba Conotoxin EpI: Ring-Closing Metathesis of Sidechain Deprotected, Sulfide-Rich Sequences
by Amy L. Thomson, Andrea J. Robinson and Alessia Belgi
Mar. Drugs 2023, 21(7), 390; https://doi.org/10.3390/md21070390 - 29 Jun 2023
Cited by 1 | Viewed by 1167
Abstract
Recombinant peptide synthesis allows for large-scale production of peptides with therapeutic potential. However, access to dicarba peptidomimetics via sidechain-deprotected sequences becomes challenging with exposed Lewis basicity presented by amine and sulfur-containing residues. Presented here is a combination of strategies which can be used [...] Read more.
Recombinant peptide synthesis allows for large-scale production of peptides with therapeutic potential. However, access to dicarba peptidomimetics via sidechain-deprotected sequences becomes challenging with exposed Lewis basicity presented by amine and sulfur-containing residues. Presented here is a combination of strategies which can be used to deactivate coordinative residues and achieve high-yielding Ru-catalyzed ring-closing metathesis. The chemistry is exemplified using α-conotoxin EpI, a native bicyclic disulfide-containing sequence isolated from the marine conesnail Conus episcopatus. Replacement of the loop I disulfide with E/Z–dicarba bridges was achieved with high conversion via solution-phase ring-closing metathesis of the unprotected linear peptide after simple chemoselective oxidation and ion-exchange masking of problematic functionality. Metathesis was also attempted in green solvent choices to further improve the sustainability of dicarba peptide synthesis. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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12 pages, 1670 KiB  
Article
Synthesis and Biological Activity of Novel α-Conotoxins Derived from Endemic Polynesian Cone Snails
by Yazid Mohamed Souf, Gonxhe Lokaj, Veeresh Kuruva, Yakop Saed, Delphine Raviglione, Ashraf Brik, Annette Nicke, Nicolas Inguimbert and Sébastien Dutertre
Mar. Drugs 2023, 21(6), 356; https://doi.org/10.3390/md21060356 - 9 Jun 2023
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Abstract
α-Conotoxins are well-known probes for the characterization of the various subtypes of nicotinic acetylcholine receptors (nAChRs). Identifying new α-conotoxins with different pharmacological profiles can provide further insights into the physiological or pathological roles of the numerous nAChR isoforms found at the neuromuscular junction, [...] Read more.
α-Conotoxins are well-known probes for the characterization of the various subtypes of nicotinic acetylcholine receptors (nAChRs). Identifying new α-conotoxins with different pharmacological profiles can provide further insights into the physiological or pathological roles of the numerous nAChR isoforms found at the neuromuscular junction, the central and peripheral nervous systems, and other cells such as immune cells. This study focuses on the synthesis and characterization of two novel α-conotoxins obtained from two species endemic to the Marquesas Islands, namely Conus gauguini and Conus adamsonii. Both species prey on fish, and their venom is considered a rich source of bioactive peptides that can target a wide range of pharmacological receptors in vertebrates. Here, we demonstrate the versatile use of a one-pot disulfide bond synthesis to achieve the α-conotoxin fold [Cys 1-3; 2-4] for GaIA and AdIA, using the 2-nitrobenzyl (NBzl) protecting group of cysteines for effective regioselective oxidation. The potency and selectivity of GaIA and AdIA against rat nicotinic acetylcholine receptors were investigated electrophysiologically and revealed potent inhibitory activities. GaIA was most active at the muscle nAChR (IC50 = 38 nM), whereas AdIA was most potent at the neuronal α6/3 β2β3 subtype (IC50 = 177 nM). Overall, this study contributes to a better understanding of the structure–activity relationships of α-conotoxins, which may help in the design of more selective tools. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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13 pages, 2524 KiB  
Article
Substitution of D-Arginine at Position 11 of α-RgIA Potently Inhibits α7 Nicotinic Acetylcholine Receptor
by Yong Wu, Junjie Zhang, Jie Ren, Xiaopeng Zhu, Rui Li, Dongting Zhangsun and Sulan Luo
Mar. Drugs 2023, 21(6), 326; https://doi.org/10.3390/md21060326 - 26 May 2023
Cited by 1 | Viewed by 1244
Abstract
Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown [...] Read more.
Conotoxins are a class of disulfide-rich peptides found in the venom of cone snails, which have attracted considerable attention in recent years due to their potent activity on ion channels and potential for therapeutics. Among them, α-conotoxin RgIA, a 13-residue peptide, has shown great promise as a potent inhibitor of α9α10 nAChRs for pain management. In this study, we investigated the effect of substituting the naturally occurring L-type arginine at position 11 of the RgIA sequence with its D-type amino acid. Our results indicate that this substitution abrogated the ability of RgIA to block α9α10 nAChRs, but instead endowed the peptide with the ability to block α7 nAChR activity. Structural analyses revealed that this substitution induced significant alteration of the secondary structure of RgIA[11r], which consequently affected its activity. Our findings underscore the potential of D-type amino acid substitution as a promising strategy for designing novel conotoxin-based ligands targeting different types of nAChRs. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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14 pages, 2053 KiB  
Article
Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID
by Jianying Dong, Panpan Zhang, Junjie Xie, Ting Xie, Xiaopeng Zhu, Dongting Zhangsun, Jinpeng Yu and Sulan Luo
Mar. Drugs 2023, 21(5), 286; https://doi.org/10.3390/md21050286 - 1 May 2023
Cited by 1 | Viewed by 1537
Abstract
α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC50 values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency [...] Read more.
α4/6-conotoxin TxID, which was identified from Conus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC50 values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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13 pages, 2838 KiB  
Article
Self-Assembly Nanostructure of Myristoylated ω-Conotoxin MVIIA Increases the Duration of Efficacy and Reduces Side Effects
by Xiufang Ding, Yue Wang, Sida Zhang, Ruihua Zhang, Dong Chen, Long Chen, Yu Zhang, Shi-Zhong Luo, Jianfu Xu and Chengxin Pei
Mar. Drugs 2023, 21(4), 229; https://doi.org/10.3390/md21040229 - 1 Apr 2023
Cited by 4 | Viewed by 1560
Abstract
Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, [...] Read more.
Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, severe neurological side effects and low stability associated with peptide MVIIA have restricted its widespread use. Fortunately, self-assembly endows the peptide with high stability and multiple functions, which can effectively control its release to prolong its duration of action. Inspired by this, MVIIA was modified with appropriate fatty acid chains to render it amphiphilic and easier to self-assemble. In this paper, an N-terminal myristoylated MVIIA (Myr-MVIIA, medium carbon chain length) was designed and prepared to undergo self-assembly. The present results indicated that Myr-MVIIA can self-assemble into micelles. Self-assembled micelles formed by Myr-MVIIA at higher concentrations than MVIIA can prolong the duration of the analgesic effect and significantly reduce or even eliminate the side effects of tremor and coordinated motor dysfunction in mice. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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17 pages, 2430 KiB  
Review
Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism
by Francesco Margiotta, Laura Micheli, Clara Ciampi, Carla Ghelardini, J. Michael McIntosh and Lorenzo Di Cesare Mannelli
Mar. Drugs 2022, 20(12), 773; https://doi.org/10.3390/md20120773 - 10 Dec 2022
Cited by 5 | Viewed by 2467
Abstract
Conus regius is a marine venomous mollusk of the Conus genus that captures its prey by injecting a rich cocktail of bioactive disulfide bond rich peptides called conotoxins. These peptides selectively target a broad range of ion channels, membrane receptors, transporters, and enzymes, [...] Read more.
Conus regius is a marine venomous mollusk of the Conus genus that captures its prey by injecting a rich cocktail of bioactive disulfide bond rich peptides called conotoxins. These peptides selectively target a broad range of ion channels, membrane receptors, transporters, and enzymes, making them valuable pharmacological tools and potential drug leads. C. regius-derived conotoxins are particularly attractive due to their marked potency and selectivity against specific nicotinic acetylcholine receptor subtypes, whose signalling is involved in pain, cognitive disorders, drug addiction, and cancer. However, the species-specific differences in sensitivity and the low stability and bioavailability of these conotoxins limit their clinical development as novel therapeutic agents for these disorders. Here, we give an overview of the main pharmacological features of the C. regius-derived conotoxins described so far, focusing on the molecular mechanisms underlying their potential therapeutic effects. Additionally, we describe adoptable chemical engineering solutions to improve their pharmacological properties for future potential clinical translation. Full article
(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)
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