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Special Issue "Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea"

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

Deadline for manuscript submissions: 25 November 2023 | Viewed by 5940

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Special Issue Editors

Dr. Alessia Belgi

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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

Prof. Dr. Andrea Jane Robinson

E-Mail Website
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 GABA_B 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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

conotoxin
conotoxin analogue
novel conotoxin
conotoxin mimetic
mode of action

Published Papers (6 papers)

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Research

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Open AccessArticle

Synthesis of Cystine-Stabilised Dicarba Conotoxin EpI: Ring-Closing Metathesis of Sidechain Deprotected, Sulfide-Rich Sequences

Amy L. Thomson

Andrea J. Robinson

and

Alessia Belgi

Mar. Drugs 2023, 21(7), 390; https://doi.org/10.3390/md21070390 - 29 Jun 2023

Viewed by 558

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 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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Open AccessArticle

Synthesis and Biological Activity of Novel α-Conotoxins Derived from Endemic Polynesian Cone Snails

and

Mar. Drugs 2023, 21(6), 356; https://doi.org/10.3390/md21060356 - 09 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, 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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Open AccessArticle

Substitution of D-Arginine at Position 11 of α-RgIA Potently Inhibits α7 Nicotinic Acetylcholine Receptor

and

Mar. Drugs 2023, 21(6), 326; https://doi.org/10.3390/md21060326 - 26 May 2023

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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 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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Open AccessArticle

Loop2 Size Modification Reveals Significant Impacts on the Potency of α-Conotoxin TxID

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Mar. Drugs 2023, 21(5), 286; https://doi.org/10.3390/md21050286 - 01 May 2023

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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 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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Open AccessArticle

Self-Assembly Nanostructure of Myristoylated ω-Conotoxin MVIIA Increases the Duration of Efficacy and Reduces Side Effects

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Mar. Drugs 2023, 21(4), 229; https://doi.org/10.3390/md21040229 - 01 Apr 2023

Viewed by 887

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 (Ca_v2.2), 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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Conus regius-Derived Conotoxins: Novel Therapeutic Opportunities from a Marine Organism

and

Lorenzo Di Cesare Mannelli

Mar. Drugs 2022, 20(12), 773; https://doi.org/10.3390/md20120773 - 10 Dec 2022

Cited by 2 | Viewed by 1503

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, 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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Special Issue "Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea"

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