Submit to Marine Drugs Review for Marine Drugs Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

Conotoxins II

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Related Special Issue
Published Papers

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 19207

Share This Special Issue

Special Issue Editors

Prof. Dr. David Adams

E-Mail Website
Guest Editor

Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, NSW 2522, Australia
Interests: acetylcholine nicotinic receptors; voltage-gated ion channels; venom peptides; conotoxins; structure-function relationship; electrophysiology; nociception
Special Issues, Collections and Topics in MDPI journals

Dr. Quentin Kaas

E-Mail Website
Guest Editor

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia
Interests: venom peptides; conopeptides; ion channels; structure-function relationships; bioinformatics; molecular modelling; NMR spectroscopy; peptide de novo design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Each of the 1000 known species of carnivorous marine cone snails produce an abundant, diverse, and mostly unique armada of peptide toxins for defence and prey capture. These disulphide-rich peptides, called conotoxins, have potent and selective activity at various targets of the nervous system, including ion channels and G-protein-coupled receptors. Several conotoxins have entered clinical trials for their analgesic properties, and one conotoxin (MVIIA (ziconotide)), is used in the clinic to treat intractable chronic pain. Only ca. 200 conotoxins have been functionally characterised out of the ca. 3000 conotoxins that have hitherto been discovered, noting that the total pool of wild-type distinct conotoxins is probably close to 100,000. In recent years, progress in high-resolution electron microscopy techniques has enabled the characterisation of the three-dimensional complexes between conotoxins and their molecular targets, supporting the design of conotoxin variants with improved pharmaceutical properties. Conotoxins are a bustling research field, and this Special Issue of Marine Drugs aims to collect articles and focused reviews on the activity and design of conotoxins.

Prof. Dr. David Adams
Dr. Quentin Kaas
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

Cone snail
Conopeptide
Structure–activity relationships
Electrophysiology
Analgesic

Related Special Issue

Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads in Marine Drugs (11 articles)

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

14 pages, 1837 KiB

Open AccessArticle

Usage of Cell-Free Protein Synthesis in Post-Translational Modification of μ-Conopeptide PIIIA

by Yanli Liu, Zitong Zhao, Yunyang Song, Yifeng Yin, Fanghui Wu and Hui Jiang

Mar. Drugs 2023, 21(8), 421; https://doi.org/10.3390/md21080421 - 25 Jul 2023

Viewed by 1033

Abstract

The post-translational modifications of conopeptides are the most complicated modifications to date and are well-known and closely related to the activity of conopeptides. The hydroxylation of proline in conopeptides affects folding, structure, and biological activity, and prolyl 4 hydroxylase has been characterized in Conus literatus. However, the hydroxylation machinery of proline in conopeptides is still unclear. In order to address the hydroxylation mechanism of proline in μ-PIIIA, three recombinant plasmids encoding different hybrid precursors of μ-PIIIA were constructed and crossly combined with protein disulfide isomerase, prolyl 4 hydroxylase, and glutaminyl cyclase in a continuous exchange cell-free protein system. The findings showed that prolyl 4 hydroxylase might recognize the propeptide of μ-PIIIA to achieve the hydroxylation of proline, while the cyclization of glutamate was also formed. Additionally, in Escherichia coli, the co-expression plasmid encoding prolyl 4 hydroxylase and the precursor of μ-PIIIA containing pro and mature regions were used to validate the continuous exchange cell-free protein system. Surprisingly, in addition to the two hydroxyproline residues and one pyroglutamyl residue, three disulfide bridges were formed using Trx as a fusion tag, and the yield of the fusion peptide was approximately 20 mg/L. The results of electrophysiology analysis indicated that the recombinant μ-PIIIA without C-terminal amidate inhibited the current of hNa_V1.4 with a 939 nM IC₅₀. Our work solved the issue that it was challenging to quickly generate post-translationally modified conopeptides in vitro. This is the first study to demonstrate that prolyl 4 hydroxylase catalyzes the proline hydroxylation through recognition in the propeptide of μ-PIIIA, and it will provide a new way for synthesizing multi-modified conopeptides with pharmacological activity. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Figure 1

15 pages, 4633 KiB

Open AccessArticle

Characterisation of Elevenin-Vc1 from the Venom of Conus victoriae: A Structural Analogue of α-Conotoxins

by Bankala Krishnarjuna, Punnepalli Sunanda, Jeffrey Seow, Han-Shen Tae, Samuel D. Robinson, Alessia Belgi, Andrea J. Robinson, Helena Safavi-Hemami, David J. Adams and Raymond S. Norton

Mar. Drugs 2023, 21(2), 81; https://doi.org/10.3390/md21020081 - 25 Jan 2023

Cited by 2 | Viewed by 1519

Abstract

Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, and molluscs. They consist of 17 to 19 amino acid residues with a single conserved disulfide bond. The subject of this study, elevenin-Vc1, was first identified in the venom of the cone snail Conus victoriae (Gen. Comp. Endocrinol. 2017, 244, 11–18). Although numerous elevenin sequences have been reported, their physiological function is unclear, and no structural information is available. Upon intracranial injection in mice, elevenin-Vc1 induced hyperactivity at doses of 5 or 10 nmol. The structure of elevenin-Vc1, determined using nuclear magnetic resonance spectroscopy, consists of a short helix and a bend region stabilised by the single disulfide bond. The elevenin-Vc1 structural fold is similar to that of α-conotoxins such as α-RgIA and α-ImI, which are also found in the venoms of cone snails and are antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). In an attempt to mimic the functional motif, Asp-Pro-Arg, of α-RgIA and α-ImI, we synthesised an analogue, designated elevenin-Vc1-DPR. However, neither elevenin-Vc1 nor the analogue was active at six different human nAChR subtypes (α1β1εδ, α3β2, α3β4, α4β2, α7, and α9α10) at 1 µM concentrations. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Graphical abstract

14 pages, 2269 KiB

Open AccessArticle

Characterization of the Native Disulfide Isomers of the Novel χ-Conotoxin PnID: Implications for Further Increasing Conotoxin Diversity

by Michael J. Espiritu, Jonathan K. Taylor, Christopher K. Sugai, Parashar Thapa, Nikolaus M. Loening, Emma Gusman, Zenaida G. Baoanan, Michael H. Baumann and Jon-Paul Bingham

Mar. Drugs 2023, 21(2), 61; https://doi.org/10.3390/md21020061 - 19 Jan 2023

Cited by 1 | Viewed by 1760

Abstract

χ-Conotoxins are known for their ability to selectively inhibit norepinephrine transporters, an ability that makes them potential leads for treating various neurological disorders, including neuropathic pain. PnID, a peptide isolated from the venom of Conus pennaceus, shares high sequence homology with previously characterized χ-conotoxins. Whereas previously reported χ-conotoxins seem to only have a single native disulfide bonding pattern, PnID has three native isomers due to the formation of different disulfide bond patterns during its maturation in the venom duct. In this study, the disulfide connectivity and three-dimensional structure of these disulfide isomers were explored using regioselective synthesis, chromatographic coelution, and solution-state nuclear magnetic resonance spectroscopy. Of the native isomers, only the isomer with a ribbon disulfide configuration showed pharmacological activity similar to other χ-conotoxins. This isomer inhibited the rat norepinephrine transporter (IC₅₀ = 10 ± 2 µM) and has the most structural similarity to previously characterized χ-conotoxins. In contrast, the globular isoform of PnID showed more than ten times less activity against this transporter and the beaded isoform did not display any measurable biological activity. This study is the first report of the pharmacological and structural characterization of an χ-conotoxin from a species other than Conus marmoreus and is the first report of the existence of natively-formed conotoxin isomers. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Graphical abstract

12 pages, 2317 KiB

Open AccessArticle

A Single Amino Acid Replacement Boosts the Analgesic Activity of α-Conotoxin AuIB through the Inhibition of the GABA_BR-Coupled N-Type Calcium Channel

by Yuanmei Wei, Min Zhang, Shuo Yu, Qiuyuan Huang, Rongfang Chen, Shujing Xu, Yue Huang, Yunzhou Yu, Ming Liao and Qiuyun Dai

Mar. Drugs 2022, 20(12), 750; https://doi.org/10.3390/md20120750 - 29 Nov 2022

Cited by 1 | Viewed by 1504

Abstract

α-conotoxin AuIB is the only one of the 4/6 type α-conotoxins (α-CTxs) that inhibits the γ-aminobutyric acid receptor B (GABA_BR)-coupled N-type calcium channel (Ca_V2.2). To improve its inhibitory activity, a series of variants were synthesized and evaluated according to the structure–activity relationships of 4/7 type α-CTxs targeting GABA_BR-coupled Ca_V2.2. Surprisingly, only the substitution of Pro7 with Arg results in a 2–3-fold increase in the inhibition of GABA_BR-coupled Ca_V2.2 (IC₅₀ is 0.74 nM); substitutions of position 9–12 with basic or hydrophobic amino acid and the addition of hydrophobic amino acid Leu or Ile at the second loop to mimic 4/7 type α-CTxs all failed to improve the inhibitory activity of AuIB against GABA_BR-coupled Ca_V2.2. Interestingly, the most potent form of AuIB[P7R] has disulfide bridges of “1–4, 2–3” (ribbon), which differs from the “1–3, 2–4” (globular) in the isoforms of wildtype AuIB. In addition, AuIB[P7R](globular) displays potent analgesic activity in the acetic acid writhing model and the partial sciatic nerve injury (PNL) model. Our study demonstrated that 4/6 type α-CTxs, with the disulfide bridge connectivity “1–4, 2–3,” are also potent inhibitors for GABA_BR-coupled Ca_V2.2, exhibiting potent analgesic activity. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Figure 1

18 pages, 4780 KiB

Open AccessArticle

Inflammation Regulation via an Agonist and Antagonists of α7 Nicotinic Acetylcholine Receptors in RAW264.7 Macrophages

by Yao Tan, Zhaoli Chu, Hongyu Shan, Dongting Zhangsun, Xiaopeng Zhu and Sulan Luo

Mar. Drugs 2022, 20(3), 200; https://doi.org/10.3390/md20030200 - 09 Mar 2022

Cited by 5 | Viewed by 3268

Abstract

The α7 nicotinic acetylcholine receptor (nAChR) is widely distributed in the central and peripheral nervous systems and is closely related to a variety of nervous system diseases and inflammatory responses. The α7 nAChR subtype plays a vital role in the cholinergic anti-inflammatory pathway. In vivo, ACh released from nerve endings stimulates α7 nAChR on macrophages to regulate the NF-κB and JAK2/STAT3 signaling pathways, thereby inhibiting the production and release of downstream proinflammatory cytokines and chemokines. Despite a considerable level of recent research on α7 nAChR-mediated immune responses, much is still unknown. In this study, we used an agonist (PNU282987) and antagonists (MLA and α-conotoxin [A10L]PnIA) of α7 nAChR as pharmacological tools to identify the molecular mechanism of the α7 nAChR-mediated cholinergic anti-inflammatory pathway in RAW264.7 mouse macrophages. The results of quantitative PCR, ELISAs, and transcriptome analysis were combined to clarify the function of α7 nAChR regulation in the inflammatory response. Our findings indicate that the agonist PNU282987 significantly reduced the expression of the IL-6 gene and protein in inflammatory macrophages to attenuate the inflammatory response, but the antagonists MLA and α-conotoxin [A10L]PnIA had the opposite effects. Neither the agonist nor antagonists of α7 nAChR changed the expression level of the α7 nAChR subunit gene; they only regulated receptor function. This study provides a reference and scientific basis for the discovery of novel α7 nAChR agonists and their anti-inflammatory applications in the future. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Graphical abstract

11 pages, 3956 KiB

Open AccessArticle

Computational Design of High-Affinity Blockers for Sodium Channel Na_V1.2 from μ-Conotoxin KIIIA

by Guangsi Meng and Serdar Kuyucak

Mar. Drugs 2022, 20(2), 154; https://doi.org/10.3390/md20020154 - 21 Feb 2022

Viewed by 1976

Abstract

The voltage-gated sodium channel subtype 1.2 (Na_V1.2) is instrumental in the initiation of action potentials in the nervous system, making it a natural drug target for neurological diseases. Therefore, there is much pharmacological interest in finding blockers of Na_V1.2 and improving their affinity and selectivity properties. An extensive family of peptide toxins from cone snails (conotoxins) block Na_V channels, thus they provide natural templates for the design of drugs targeting Na_V channels. Unfortunately, progress was hampered due to the absence of any Na_V structures. The recent determination of cryo-EM structures for Na_V channels has finally broken this impasse. Here, we use the Na_V1.2 structure in complex with μ-conotoxin KIIIA (KIIIA) in computational studies with the aim of improving KIIIA’s affinity and blocking capacity for Na_V1.2. Only three KIIIA amino acid residues are available for mutation (S5, S6, and S13). After performing molecular modeling and simulations on Na_V1.2–KIIIA complex, we have identified the S5R, S6D, and S13K mutations as the most promising for additional contacts. We estimate these contacts to boost the affinity of KIIIA for Na_V1.2 from nanomole to picomole domain. Moreover, the KIIIA[S5R, S6D, S13K] analogue makes contacts with all four channel domains, thus enabling the complete blocking of the channel (KIIIA partially blocks as it has contacts with three domains). The proposed KIIIA analogue, once confirmed experimentally, may lead to novel anti-epileptic drugs. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Figure 1

9 pages, 1280 KiB

Open AccessArticle

A Novel α4/7-Conotoxin QuIA Selectively Inhibits α3β2 and α6/α3β4 Nicotinic Acetylcholine Receptor Subtypes with High Efficacy

by Liujun Wang, Xixi Wu, Xiaopeng Zhu, Dongting Zhangsun, Yong Wu and Sulan Luo

Mar. Drugs 2022, 20(2), 146; https://doi.org/10.3390/md20020146 - 17 Feb 2022

Cited by 2 | Viewed by 1614

Abstract

α6β4 nAChR is expressed in the peripheral and central nervous systems and is associated with pain, addiction, and movement disorders. Natural α-conotoxins (α-CTxs) can effectively block different nAChR subtypes with higher efficacy and selectivity. However, the research on α6β4 nAChR is relatively poor, partly because of the lack of available target-specific α-CTxs. In this study, we synthesized a novel α-4/7 conotoxin QuIA that was found from Conus quercinus. We investigated the efficacy of this peptide to different nAChR subtypes using a two-electrode voltage-clamp technique. Remarkably, we found α-QuIA inhibited the neuronal α3β2 and α6/α3β4 nAChR subtypes with significantly high affinity (IC₅₀ was 55.7 nM and 90.68 nM, respectively), and did not block other nAChR subtypes even at a high concentration of 10 μM. In contrast, most α-CTxs have been determined so far to effectively block the α6/α3β4 nAChR subtype while also maintaining a similar higher efficacy against the closely related α6β2β3 and/or α3β4 subtypes, which are different from QuIA. In conclusion, α-QuIA is a novel α4/7-CTx, which has the potential to develop as an effective neuropharmacology tool to detect the function of α6β4 nAChR. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Figure 1

Review

Jump to: Research

15 pages, 2823 KiB

Open AccessReview

Bibliometric Review of the Literature on Cone Snail Peptide Toxins from 2000 to 2022

by Linh T. T. Nguyen, David J. Craik and Quentin Kaas

Mar. Drugs 2023, 21(3), 154; https://doi.org/10.3390/md21030154 - 25 Feb 2023

Cited by 4 | Viewed by 2580

Abstract

The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain ramped up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Figure 1

20 pages, 7849 KiB

Open AccessReview

Conotoxin Patenting Trends in Academia and Industry

by Noemi Sanchez-Campos, Johanna Bernaldez-Sarabia and Alexei F. Licea-Navarro

Mar. Drugs 2022, 20(8), 531; https://doi.org/10.3390/md20080531 - 19 Aug 2022

Cited by 4 | Viewed by 2672

Abstract

Sea snails of the genus Conus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since Conus toxins were discovered in the 1960s, their biological activity has been thought to have high pharmaceutical potential that could be explored beyond the limits of academic laboratories. We reviewed 224 patent documents related to conotoxins and conopeptides globally to determine the course that innovation and development has taken over the years, their primary applications, the technological trends over the last six years, and the leaders in the field, since the only previous patent review was performed in 2015 and focused in USA valid patents. In addition, we explored which countries/territories protect their inventions and patents and the most relevant collaborations among assignees. We also evaluated whether academia or pharmaceutical companies are the future of conotoxin research. We concluded that the 224 conotoxin patents reviewed in this study have more academic value than industrial value, which was noted by the number of active patents that have not yet been licensed and the contributions to medical research, especially as tools to study neuropathic pain, inflammation, immunology, drug design, receptor binding sites, cancer, neurotransmission, epilepsy, peptide biosynthesis, and depression. The aim of this review is to provide an overview of the current state of conotoxin patents, their main applications, and success based on the number of licensing and products in the market. Full article

(This article belongs to the Special Issue Conotoxins II)

► Show Figures

Journal Menu

Journal Browser

Conotoxins II

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Related Special Issue

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI