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Marine Drugs
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Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads
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Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 35089

Special Issue Editor

Dr. Quentin Kaas

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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,

The venom of marine cone snails is the largest known source of peptide toxins from marine animals. Conotoxins, more broadly defined as conopeptides, have diverse and potent activities against a range of targets that are of major interest for pharmaceutical applications, especially ion channels, transporters and GPCRs. Some cone snail peptides are actively developed as drug leads, and conotoxin MVIIA is an approved medication for managing severe chronic pain. Considerable efforts have been made to modify conopeptides toward medical applications, with the notable success of engineered conopeptide Vc1.1 displaying oral activity. The interactions between some conopeptides and their targets is studied in increasingly greater molecular details, enabling the rational design of conopeptide activity. At the same time, conopeptides with new activities are constantly discovered in the pool of wild-type toxins, the surface of which has barely been scratched. For example, conotoxins GVIIJ identified in the transcriptome of Conus Geographus potently blocks sodium channels by forming a covalent bond with the channel. The recent discovery that cone snails have two types of venoms for either attack or defense offers new spaces for mining conopeptides. This Special Issue on cone snail venom peptides aims at collecting exciting new discoveries in the field, ranging from multiomics exploration of cone snail venoms to characterization and engineering of conopeptide pharmaceutical wonders toward the development of lead compounds.

Dr. Quentin Kaas
Guest Editor

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Keywords

  • conopeptide
  • conotoxin
  • toxin
  • Conus
  • ion channel
  • structure-activity relationship
  • venom duct
  • venom gland
  • ziconotide
  • MVIIA
  • transcriptomics
  • proteomics
  • electrophysiology
  • solid-phase peptide synthesis
  • bioinformatics
  • nuclear magnetic resonance
  • molecular modelling

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Related Special Issue

Published Papers (11 papers)

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Research

15 pages, 2246 KiB  
Article
Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy
by Md. Mahadhi Hasan, Hana Starobova, Alexander Mueller, Irina Vetter and Richard J. Lewis
Mar. Drugs 2021, 19(2), 106; https://doi.org/10.3390/md19020106 - 11 Feb 2021
Cited by 16 | Viewed by 3404
Abstract
The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw [...] Read more.
The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p < 0.0001, p < 0.0001, and p < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p < 0.0001, p < 0.01, and p < 0.05, respectively), and 300 nM and 100 nM GVIA (p < 0.0001 and p < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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14 pages, 4076 KiB  
Article
Chemical Synthesis and NMR Solution Structure of Conotoxin GXIA from Conus geographus
by David A. Armstrong, Ai-Hua Jin, Nayara Braga Emidio, Richard J. Lewis, Paul F. Alewood and K. Johan Rosengren
Mar. Drugs 2021, 19(2), 60; https://doi.org/10.3390/md19020060 - 26 Jan 2021
Cited by 5 | Viewed by 2714
Abstract
Conotoxins are disulfide-rich peptides found in the venom of cone snails. Due to their exquisite potency and high selectivity for a wide range of voltage and ligand gated ion channels they are attractive drug leads in neuropharmacology. Recently, cone snails were found to [...] Read more.
Conotoxins are disulfide-rich peptides found in the venom of cone snails. Due to their exquisite potency and high selectivity for a wide range of voltage and ligand gated ion channels they are attractive drug leads in neuropharmacology. Recently, cone snails were found to have the capability to rapidly switch between venom types with different proteome profiles in response to predatory or defensive stimuli. A novel conotoxin, GXIA (original name G117), belonging to the I3-subfamily was identified as the major component of the predatory venom of piscivorous Conus geographus. Using 2D solution NMR spectroscopy techniques, we resolved the 3D structure for GXIA, the first structure reported for the I3-subfamily and framework XI family. The 32 amino acid peptide is comprised of eight cysteine residues with the resultant disulfide connectivity forming an ICK+1 motif. With a triple stranded β-sheet, the GXIA backbone shows striking similarity to several tarantula toxins targeting the voltage sensor of voltage gated potassium and sodium channels. Supported by an amphipathic surface, the structural evidence suggests that GXIA is able to embed in the membrane and bind to the voltage sensor domain of a putative ion channel target. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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15 pages, 3375 KiB  
Article
A Conantokin Peptide Con-T[M8Q] Inhibits Morphine Dependence with High Potency and Low Side Effects
by Zhuguo Liu, Zheng Yu, Shuo Yu, Cui Zhu, Mingxin Dong, Wenxiang Mao, Jie Hu, Mary Prorok, Ruibin Su and Qiuyun Dai
Mar. Drugs 2021, 19(1), 44; https://doi.org/10.3390/md19010044 - 19 Jan 2021
Cited by 7 | Viewed by 2809
Abstract
N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a [...] Read more.
N-methyl-D-aspartate receptor (NMDAR) antagonists have been found to be effective to inhibit morphine dependence. However, the discovery of the selective antagonist for NMDAR GluN2B with low side-effects still remains challenging. In the present study, we report a selective NMDAR GluN2B antagonist con-T[M8Q](a conantokin-T variant) that potently inhibits the naloxone-induced jumping and conditioned place preference of morphine-dependent mice at nmol/kg level, 100-fold higher than ifenprodil, a classical NMDAR NR2B antagonist. Con-T[M8Q] displays no significant impacts on coordinated locomotion function, spontaneous locomotor activity, and spatial memory mice motor function at the dose used. Further molecular mechanism experiments demonstrate that con-T[M8Q] effectively inhibited the transcription and expression levels of signaling molecules related to NMDAR NR2B subunit in hippocampus, including NR2B, p-NR2B, CaMKII-α, CaMKII-β, CaMKIV, pERK, and c-fos. The high efficacy and low side effects of con-T[M8Q] make it a good lead compound for the treatment of opiate dependence and for the reduction of morphine usage. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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10 pages, 1593 KiB  
Article
Binding of κ-Conotoxin-PVIIA to Open and Closed Shaker K-Channels Are Differentially Affected by the Ionic Strength
by David Naranjo and Ignacio Díaz-Franulic
Mar. Drugs 2020, 18(11), 533; https://doi.org/10.3390/md18110533 - 26 Oct 2020
Cited by 5 | Viewed by 2091
Abstract
κ-Conotoxin-PVIIA (κ-PVIIA) is a potassium-channel blocking peptide from the venom of the fish-hunting snail, Conus purpurascens, which is essential for quick prey’s excitotoxic immobilization. Binding of one κ-PVIIA to Shaker K-channels occludes the K+-conduction pore without additional conformational effects. Because [...] Read more.
κ-Conotoxin-PVIIA (κ-PVIIA) is a potassium-channel blocking peptide from the venom of the fish-hunting snail, Conus purpurascens, which is essential for quick prey’s excitotoxic immobilization. Binding of one κ-PVIIA to Shaker K-channels occludes the K+-conduction pore without additional conformational effects. Because this 27-residue toxin is +4-charged at neutral pH, we asked if electrostatic interactions play a role in binding. With Voltage-Clamp electrophysiology, we tested how ionic strength (IS) affects κ-PVIIA blockade to Shaker. When IS varied from ~0.06 to ~0.16 M, the dissociation constant for open and closed channels increased by ~5- and ~16-fold, respectively. While the association rates decreased equally, by ~4-fold, in open and closed channels, the dissociation rates increased 4–5-fold in closed channels but was IS-insensitive in open channels. To explain this differential IS-dependency, we propose that the bound κ-PVIIA wobbles, so that in open channels the intracellular environment, via ion-conduction pore, buffers the imposed IS-changes in the toxin-channel interface. A Brønsted-Bjerrum analysis on the rates predicts that if, instead of fish, the snail preyed on organisms with seawater-like lymph ionic composition, a severely harmless toxin, with >100-fold diminished affinity, would result. Thus, considerations of the native ionic environment are essential for conotoxins evaluation as pharmacological leads. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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7 pages, 592 KiB  
Communication
Studies of Conorfamide-Sr3 on Human Voltage-Gated Kv1 Potassium Channel Subtypes
by Estuardo López-Vera, Luis Martínez-Hernández, Manuel B. Aguilar, Elisa Carrillo and Joanna Gajewiak
Mar. Drugs 2020, 18(8), 425; https://doi.org/10.3390/md18080425 - 13 Aug 2020
Cited by 9 | Viewed by 2661
Abstract
Recently, Conorfamide-Sr3 (CNF-Sr3) was isolated from the venom of Conus spurius and was demonstrated to have an inhibitory concentration-dependent effect on the Shaker K+ channel. The voltage-gated potassium channels play critical functions on cellular signaling, from the regeneration of action potentials in [...] Read more.
Recently, Conorfamide-Sr3 (CNF-Sr3) was isolated from the venom of Conus spurius and was demonstrated to have an inhibitory concentration-dependent effect on the Shaker K+ channel. The voltage-gated potassium channels play critical functions on cellular signaling, from the regeneration of action potentials in neurons to the regulation of insulin secretion in pancreatic cells, among others. In mammals, there are at least 40 genes encoding voltage-gated K+ channels and the process of expression of some of them may include alternative splicing. Given the enormous variety of these channels and the proven use of conotoxins as tools to distinguish different ligand- and voltage-gated ion channels, in this work, we explored the possible effect of CNF-Sr3 on four human voltage-gated K+ channel subtypes homologous to the Shaker channel. CNF-Sr3 showed a 10 times higher affinity for the Kv1.6 subtype with respect to Kv1.3 (IC50 = 2.7 and 24 μM, respectively) and no significant effect on Kv1.4 and Kv1.5 at 10 µM. Thus, CNF-Sr3 might become a novel molecular probe to study diverse aspects of human Kv1.3 and Kv1.6 channels. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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23 pages, 4643 KiB  
Article
Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations
by Jierong Wen, David J. Adams and Andrew Hung
Mar. Drugs 2020, 18(7), 349; https://doi.org/10.3390/md18070349 - 3 Jul 2020
Cited by 6 | Viewed by 3845
Abstract
Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)2(β2)3 nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) [...] Read more.
Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)2(β2)3 nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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11 pages, 2341 KiB  
Article
α-Conotoxins Enhance both the In Vivo Suppression of Ehrlich carcinoma Growth and In Vitro Reduction in Cell Viability Elicited by Cyclooxygenase and Lipoxygenase Inhibitors
by Alexey V. Osipov, Tatiana I. Terpinskaya, Tatsiana Yanchanka, Tatjana Balashevich, Maxim N. Zhmak, Victor I. Tsetlin and Yuri N. Utkin
Mar. Drugs 2020, 18(4), 193; https://doi.org/10.3390/md18040193 - 7 Apr 2020
Cited by 8 | Viewed by 2629
Abstract
Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein [...] Read more.
Several biochemical mechanisms, including the arachidonic acid cascade and activation of nicotinic acetylcholine receptors (nAChRs), are involved in increased tumor survival. Combined application of inhibitors acting on these two pathways may result in a more pronounced antitumor effect. Here, we show that baicalein (selective 12-lipoxygenase inhibitor), nordihydroguaiaretic acid (non-selective lipoxygenase inhibitor), and indomethacin (non-selective cyclooxygenase inhibitor) are cytotoxic to Ehrlich carcinoma cells in vitro. Marine snail α-conotoxins PnIA, RgIA and ArIB11L16D, blockers of α3β2/α6β2, α9α10 and α7 nAChR subtypes, respectively, as well as α-cobratoxin, a blocker of α7 and muscle subtype nAChRs, exhibit low cytotoxicity, but enhance the antitumor effect of baicalein 1.4-fold after 24 h and that of nordihydroguaiaretic acid 1.8–3.9-fold after 48 h of cell cultivation. α-Conotoxin MII, a blocker of α6-containing and α3β2 nAChR subtypes, increases the cytotoxic effect of indomethacin 1.9-fold after 48 h of cultivation. In vivo, baicalein, α-conotoxins MII and PnIA inhibit Ehrlich carcinoma growth and increase mouse survival; these effects are greatly enhanced by the combined application of α-conotoxin MII with indomethacin or conotoxin PnIA with baicalein. Thus, we show, for the first time, antitumor synergism of α-conotoxins and arachidonic acid cascade inhibitors. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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11 pages, 2095 KiB  
Article
Effects of Cyclization on Activity and Stability of α-Conotoxin TxIB
by Xincan Li, Shuai Wang, Xiaopeng Zhu, Dongting Zhangsun, Yong Wu and Sulan Luo
Mar. Drugs 2020, 18(4), 180; https://doi.org/10.3390/md18040180 - 29 Mar 2020
Cited by 16 | Viewed by 3021
Abstract
α-Conotoxin TxIB specifically blocked α6/α3β2β3 acetylcholine receptors (nAChRs), and it could be a potential probe for studying addiction and other diseases related to α6/α3β2β3 nAChRs. However, as a peptide, TxIB may suffer from low stability, short half-life, and poor bioavailability. In this study, [...] Read more.
α-Conotoxin TxIB specifically blocked α6/α3β2β3 acetylcholine receptors (nAChRs), and it could be a potential probe for studying addiction and other diseases related to α6/α3β2β3 nAChRs. However, as a peptide, TxIB may suffer from low stability, short half-life, and poor bioavailability. In this study, cyclization of TxIB was used to improve its stability. Four cyclic mutants of TxIB (cTxIB) were synthesized, and the inhibition of these analogues on α6/α3β2β3 nAChRs as well as their stability in human serum were measured. All cyclized analogues had similar activity compared to wild-type TxIB, which indicated that backbone cyclization of TxIB had no significant effect on its activity. Cyclization of TxIB with a seven-residue linker improved its stability significantly in human serum. Besides this, the results showed that cyclization maintained the activity of α-conotoxin TxIB, which is conducive to its future application. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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14 pages, 1035 KiB  
Article
Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR
by Xiujie Liu, Ge Yao, Kang Wang, Yanli Liu, Xiukun Wan and Hui Jiang
Mar. Drugs 2020, 18(3), 135; https://doi.org/10.3390/md18030135 - 26 Feb 2020
Cited by 7 | Viewed by 2614
Abstract
Conotoxin-Ac1 and its variant conotoxin-Ac1-O6P, were isolated from the venom duct of Conus achatinus, a fish-hunting cone snail species collected in the Sea of Hainan, China. Conotoxin-Ac1 is linear peptide that contain 15 amino acids. In the present study, we synthesized and [...] Read more.
Conotoxin-Ac1 and its variant conotoxin-Ac1-O6P, were isolated from the venom duct of Conus achatinus, a fish-hunting cone snail species collected in the Sea of Hainan, China. Conotoxin-Ac1 is linear peptide that contain 15 amino acids. In the present study, we synthesized and structurally and functionally characterized conotoxin-Ac1 as well as 19 variants. Electrophysiological results showed that conotoxin-Ac1 inhibited N-methyl-D-aspartate receptor subunit 2B (NR2B) with an IC50 of 8.22 ± 0.022 μM. Further structure-activity studies of conotoxin-Ac demonstrated that polar amino acid residues were important for modulating its active, and the replacement of N1, O9, E10, and S12 by Ala resulted in a significant decrease in potency to NR2B. °Furthermore, conotoxin-Ac1 and conotoxin-Ac1-O6P were tested in hot-plate and tail-flick assays to measure the potential analgesic activity to an acute thermal stimulus in a dose-dependent manner. Subsequently, the analgesic activity of conotoxin-Ac1 mutants was analyzed by the hot-plate method. The results show that N1, Y2, Y3, E10, N11, S12, and T15 play an important role in the analgesic activity of conotoxin-Ac1. N1 and S12 have significant effects on conotoxin-Ac1 in inhibiting NR2B and analgesic activity. In conclusion, we have discovered that conotoxin-Ac1 is an inhibitor of NMDAR and displays antinociceptive activity. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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18 pages, 2605 KiB  
Article
Ribbon α-Conotoxin KTM Exhibits Potent Inhibition of Nicotinic Acetylcholine Receptors
by Leanna A. Marquart, Matthew W. Turner, Lisa R. Warner, Matthew D. King, James R. Groome and Owen M. McDougal
Mar. Drugs 2019, 17(12), 669; https://doi.org/10.3390/md17120669 - 28 Nov 2019
Cited by 2 | Viewed by 3374
Abstract
KTM is a 16 amino acid peptide with the sequence WCCSYPGCYWSSSKWC. Here, we present the nuclear magnetic resonance (NMR) structure and bioactivity of this rationally designed α-conotoxin (α-CTx) that demonstrates potent inhibition of rat α3β2-nicotinic acetylcholine receptors (rα3β2-nAChRs). Two bioassays were used to [...] Read more.
KTM is a 16 amino acid peptide with the sequence WCCSYPGCYWSSSKWC. Here, we present the nuclear magnetic resonance (NMR) structure and bioactivity of this rationally designed α-conotoxin (α-CTx) that demonstrates potent inhibition of rat α3β2-nicotinic acetylcholine receptors (rα3β2-nAChRs). Two bioassays were used to test the efficacy of KTM. First, a qualitative PC12 cell-based assay confirmed that KTM acts as a nAChR antagonist. Second, bioactivity evaluation by two-electrode voltage clamp electrophysiology was used to measure the inhibition of rα3β2-nAChRs by KTM (IC50 = 0.19 ± 0.02 nM), and inhibition of the same nAChR isoform by α-CTx MII (IC50 = 0.35 ± 0.8 nM). The three-dimensional structure of KTM was determined by NMR spectroscopy, and the final set of 20 structures derived from 32 distance restraints, four dihedral angle constraints, and two disulfide bond constraints overlapped with a mean global backbone root-mean-square deviation (RMSD) of 1.7 ± 0.5 Å. The structure of KTM did not adopt the disulfide fold of α-CTx MII for which it was designed, but instead adopted a flexible ribbon backbone and disulfide connectivity of C2–C16 and C3–C8 with an estimated 12.5% α-helical content. In contrast, α-CTx MII, which has a native fold of C2–C8 and C3–C16, has an estimated 38.1% α-helical secondary structure. KTM is the first reported instance of a Framework I (CC-C-C) α-CTx with ribbon connectivity to display sub-nanomolar inhibitory potency of rα3β2-nAChR subtypes. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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16 pages, 2088 KiB  
Article
Conotoxin Diversity in the Venom Gland Transcriptome of the Magician’s Cone, Pionoconus magus
by José R. Pardos-Blas, Iker Irisarri, Samuel Abalde, Manuel J. Tenorio and Rafael Zardoya
Mar. Drugs 2019, 17(10), 553; https://doi.org/10.3390/md17100553 - 27 Sep 2019
Cited by 26 | Viewed by 4659
Abstract
The transcriptomes of the venom glands of two individuals of the magician’s cone, Pionoconus magus, from Okinawa (Japan) were sequenced, assembled, and annotated. In addition, RNA-seq raw reads available at the SRA database from one additional specimen of P. magus from the [...] Read more.
The transcriptomes of the venom glands of two individuals of the magician’s cone, Pionoconus magus, from Okinawa (Japan) were sequenced, assembled, and annotated. In addition, RNA-seq raw reads available at the SRA database from one additional specimen of P. magus from the Philippines were also assembled and annotated. The total numbers of identified conotoxin precursors and hormones per specimen were 118, 112, and 93. The three individuals shared only five identical sequences whereas the two specimens from Okinawa had 30 sequences in common. The total number of distinct conotoxin precursors and hormones for P. magus was 275, and were assigned to 53 conotoxin precursor and hormone superfamilies, two of which were new based on their divergent signal region. The superfamilies that had the highest number of precursors were M (42), O1 (34), T (27), A (18), O2 (17), and F (13), accounting for 55% of the total diversity. The D superfamily, previously thought to be exclusive of vermivorous cones was found in P. magus and contained a highly divergent mature region. Similarly, the A superfamily alpha 4/3 was found in P. magus despite the fact that it was previously postulated to be almost exclusive of the genus Rhombiconus. Differential expression analyses of P. magus compared to Chelyconus ermineus, the only fish-hunting cone from the Atlantic Ocean revealed that M and A2 superfamilies appeared to be more expressed in the former whereas the O2 superfamily was more expressed in the latter. Full article
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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