MDPI - Publisher of Open Access Journals

Open AccessReply Reply to the Letter “Create Guidelines for Characterization of Venom Peptides” from Dr. Volker Herzig

Toxins 2016, 8(9), 253; doi:10.3390/toxins8090253

Received: 23 August 2016 / Accepted: 23 August 2016 / Published: 30 August 2016

Viewed by 468 | PDF Full-text (172 KB) | HTML Full-text | XML Full-text

Abstract Regarding our paper “PhTx3-4, a Spider Toxin Calcium Channel Blocker, Reduces NMDA-Induced Injury of the Retina”, published in Toxins 2016, 8, doi:10.3390/toxins8030070 [1].[...] Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle The Protective Effect of Melittin on Renal Fibrosis in an Animal Model of Unilateral Ureteral Obstruction

by Hyun-Jin An, Jung-Yeon Kim, Woon-Hae Kim, Sang-Mi Han and Kwan-Kyu Park

Molecules 2016, 21(9), 1137; doi:10.3390/molecules21091137

Received: 16 July 2016 / Revised: 23 August 2016 / Accepted: 24 August 2016 / Published: 27 August 2016

Cited by 2 | Viewed by 984 | PDF Full-text (2722 KB) | HTML Full-text | XML Full-text

Abstract

Renal fibrosis is the principal pathological process underlying the progression of chronic kidney disease that leads to end-stage renal disease. Melittin is a major component of bee venom, and it has anti-bacterial, anti-viral, and anti-inflammatory properties in various cell types. Thus, this study

[...] Read more.

Renal fibrosis is the principal pathological process underlying the progression of chronic kidney disease that leads to end-stage renal disease. Melittin is a major component of bee venom, and it has anti-bacterial, anti-viral, and anti-inflammatory properties in various cell types. Thus, this study examined the therapeutic effects of melittin on the progression of renal fibrosis using the unilateral ureteral obstruction (UUO) model. In addition, the effects of melittin on inflammation and fibrosis in renal fibroblast cells were explored using transforming growth factor-β1 (TGF-β1). Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, melittin treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of inflammatory cytokines and pro-fibrotic genes were significantly reduced in melittin-treated mice compared with UUO mice. Melittin also effectively inhibited fibrosis-related gene expression in renal fibroblasts NRK-49F cells. These findings suggest that melittin attenuates renal fibrosis and reduces inflammatory responses by the suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, melittin may be a useful therapeutic agent for the prevention of fibrosis that characterizes the progression of chronic kidney disease. Full article

► Figures

Figure 1

Open AccessCase Report A Single Dose of Viperfav^TM May Be Inadequate for Vipera ammodytes Snake Bite: A Case Report and Pharmacokinetic Evaluation

by Tihana Kurtović, Miran Brvar, Damjan Grenc, Maja Lang Balija, Igor Križaj and Beata Halassy

Toxins 2016, 8(8), 244; doi:10.3390/toxins8080244

Received: 30 June 2016 / Accepted: 11 August 2016 / Published: 19 August 2016

Cited by 1 | Viewed by 803 | PDF Full-text (576 KB) | HTML Full-text | XML Full-text

Abstract

Viperfav^TM is a commercial F(ab’)₂ antivenom prepared against European vipers venom. It is safe and effective for treating envenomation caused by Vipera aspis and Vipera berus. Therapeutic efficacy for treating Vipera ammodytes ammodytes (V. a. ammodytes) envenoming has not been

[...] Read more.

Viperfav^TM is a commercial F(ab’)₂ antivenom prepared against European vipers venom. It is safe and effective for treating envenomation caused by Vipera aspis and Vipera berus. Therapeutic efficacy for treating Vipera ammodytes ammodytes (V. a. ammodytes) envenoming has not been yet described, although protective efficacy has been demonstrated in preclinical studies. We report on a 32-year-old man bitten by V. a. ammodytes who was treated with Viperfav™. Viperfav™ promptly reduced local extension and improved systemic pathological signs, but 24 h after the incident a recurrence of thrombocytopenia occurred despite a favorable pharmacokinetic profile with systemic clearance (1.64 (mL·h⁻¹)·kg⁻¹) and elimination half-life (97 h) among the highest ever reported. The recommended dose of Viperfav™ for V. aspis and V. berus bites may be inadequate for serious V. a. ammodytes envenomations. Following V. a. ammodytes bite, serial blood counts and coagulation profiles should be performed to help guide Viperfav™ treatment, along with supplemental administration as indicated. Full article

(This article belongs to the Section Animal Venoms)

► Figures

Open AccessReview A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions

by Nives Giebeler and Paola Zigrino

Toxins 2016, 8(4), 122; doi:10.3390/toxins8040122

Received: 14 March 2016 / Revised: 11 April 2016 / Accepted: 19 April 2016 / Published: 23 April 2016

Cited by 5 | Viewed by 886 | PDF Full-text (1196 KB) | HTML Full-text | XML Full-text

Abstract

Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and

[...] Read more.

Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years. Full article

(This article belongs to the Special Issue Snake Venom Metalloproteinases) Printed Edition available

Open AccessReview Jellyfish Bioactive Compounds: Methods for Wet-Lab Work

by Bárbara Frazão and Agostinho Antunes

Mar. Drugs 2016, 14(4), 75; doi:10.3390/md14040075

Received: 10 September 2015 / Revised: 3 February 2016 / Accepted: 18 February 2016 / Published: 12 April 2016

Cited by 2 | Viewed by 1496 | PDF Full-text (4332 KB) | HTML Full-text | XML Full-text

Abstract

The study of bioactive compounds from marine animals has provided, over time, an endless source of interesting molecules. Jellyfish are commonly targets of study due to their toxic proteins. However, there is a gap in reviewing successful wet-lab methods employed in these animals,

[...] Read more.

The study of bioactive compounds from marine animals has provided, over time, an endless source of interesting molecules. Jellyfish are commonly targets of study due to their toxic proteins. However, there is a gap in reviewing successful wet-lab methods employed in these animals, which compromises the fast progress in the detection of related biomolecules. Here, we provide a compilation of the most effective wet-lab methodologies for jellyfish venom extraction prior to proteomic analysis—separation, identification and toxicity assays. This includes SDS-PAGE, 2DE, gel chromatography, HPLC, DEAE, LC-MS, MALDI, Western blot, hemolytic assay, antimicrobial assay and protease activity assay. For a more comprehensive approach, jellyfish toxicity studies should further consider transcriptome sequencing. We reviewed such methodologies and other genomic techniques used prior to the deep sequencing of transcripts, including RNA extraction, construction of cDNA libraries and RACE. Overall, we provide an overview of the most promising methods and their successful implementation for optimizing time and effort when studying jellyfish. Full article

► Figures

Open AccessFeature PaperReview Heated Debates: Hot-Water Immersion or Ice Packs as First Aid for Cnidarian Envenomations?

by Christie L. Wilcox and Angel A. Yanagihara

Toxins 2016, 8(4), 97; doi:10.3390/toxins8040097

Received: 2 March 2016 / Revised: 26 March 2016 / Accepted: 29 March 2016 / Published: 1 April 2016

Cited by 5 | Viewed by 1917 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text

Abstract

Cnidarian envenomations are an important public health problem, responsible for more deaths than shark attacks annually. For this reason, optimization of first-aid care is essential. According to the published literature, cnidarian venoms and toxins are heat labile at temperatures safe for human application,

[...] Read more.

Cnidarian envenomations are an important public health problem, responsible for more deaths than shark attacks annually. For this reason, optimization of first-aid care is essential. According to the published literature, cnidarian venoms and toxins are heat labile at temperatures safe for human application, which supports the use of hot-water immersion of the sting area(s). However, ice packs are often recommended and used by emergency personnel. After conducting a systematic review of the evidence for the use of heat or ice in the treatment of cnidarian envenomations, we conclude that the majority of studies to date support the use of hot-water immersion for pain relief and improved health outcomes. Full article

(This article belongs to the Section Marine and Freshwater Toxins)

Open AccessArticle Neutralization of the Principal Toxins from the Venoms of Thai Naja kaouthia and Malaysian Hydrophis schistosus: Insights into Toxin-Specific Neutralization by Two Different Antivenoms

by Kae Yi Tan, Choo Hock Tan, Shin Yee Fung and Nget Hong Tan

Toxins 2016, 8(4), 86; doi:10.3390/toxins8040086

Received: 8 January 2016 / Revised: 6 March 2016 / Accepted: 15 March 2016 / Published: 26 March 2016

Cited by 7 | Viewed by 766 | PDF Full-text (1441 KB) | HTML Full-text | XML Full-text

Abstract

Antivenom neutralization against cobra venoms is generally low in potency, presumably due to poor toxin-specific immunoreactivity. This study aimed to investigate the effectiveness of two elapid antivenoms to neutralize the principal toxins purified from the venoms of the Thai monocled cobra (Naja

[...] Read more.

Antivenom neutralization against cobra venoms is generally low in potency, presumably due to poor toxin-specific immunoreactivity. This study aimed to investigate the effectiveness of two elapid antivenoms to neutralize the principal toxins purified from the venoms of the Thai monocled cobra (Naja kaouthia, Nk-T) and the Malaysian beaked sea snake (Hydrophis schistosus, Hs-M). In mice, N. kaouthia Monovalent Antivenom (NKMAV) neutralization against Nk-T long neurotoxin (LNTX) and cytotoxin was moderate (potency of 2.89–6.44 mg toxin/g antivenom protein) but poor against the short neurotoxin (SNTX) (1.33 mg/g). Its cross-neutralization against Hs-M LNTX of Hs-M is compatible (0.18 mg/g) but much weaker against Hs-M SNTX (0.22 mg/g). Using CSL (Seqirus Limited) Sea Snake Antivenom (SSAV), we observed consistently weak neutralization of antivenom against SNTX of both species, suggesting that this is the limiting factor on the potency of antivenom neutralization against venoms containing SNTX. Nevertheless, SSAV outperformed NKMAV in neutralizing SNTXs of both species (0.61–2.49 mg/g). The superior efficacy of SSAV against SNTX is probably partly attributable to the high abundance of SNTX in sea snake venom used as immunogen in SSAV production. The findings indicate that improving the potency of cobra antivenom may be possible with a proper immunogen formulation that seeks to overcome the limitation on SNTX immunoreactivity. Full article

(This article belongs to the Section Animal Venoms)

► Figures

Open AccessArticle DNA Aptamers against Taiwan Banded Krait α-Bungarotoxin Recognize Taiwan Cobra Cardiotoxins

by Ying-Jung Chen, Chia-Yu Tsai, Wan-Ping Hu and Long-Sen Chang

Toxins 2016, 8(3), 66; doi:10.3390/toxins8030066

Received: 31 January 2016 / Revised: 29 February 2016 / Accepted: 29 February 2016 / Published: 5 March 2016

Cited by 1 | Viewed by 981 | PDF Full-text (2015 KB) | HTML Full-text | XML Full-text

Abstract

Bungarus multicinctus α-bungarotoxin (α-Bgt) and Naja atra cardiotoxins (CTXs) share a common structural scaffold, and their tertiary structures adopt three-fingered loop motifs. Four DNA aptamers against α-Bgt have been reported previously. Given that the binding of aptamers with targeted proteins depends on structural

[...] Read more.

Bungarus multicinctus α-bungarotoxin (α-Bgt) and Naja atra cardiotoxins (CTXs) share a common structural scaffold, and their tertiary structures adopt three-fingered loop motifs. Four DNA aptamers against α-Bgt have been reported previously. Given that the binding of aptamers with targeted proteins depends on structural complementarity, in this study, we investigated whether DNA aptamers against α-Bgt could also recognize CTXs. It was found that N. atra cardiotoxin 3 (CTX3) reduced the electrophoretic mobility of aptamers against α-Bgt. Analysis of the changes in the fluorescence intensity of carboxyfluorescein-labeled aptamers upon binding toxin molecules revealed that CTX3 and α-Bgt could bind the tested aptamers. Moreover, the aptamers inhibited the membrane-damaging activity and cytotoxicity of CTX3. In addition to CTX3, other N. atra CTX isotoxins also bound to the aptamer against α-Bgt. Taken together, our data indicate that aptamers against α-Bgt show cross-reactivity with CTXs. The findings that aptamers against α-Bgt also suppress the biological activities of CTX3 highlight the potential utility of aptamers in regard to the broad inhibition of snake venom three-fingered proteins. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle A New Member of Gamma-Conotoxin Family Isolated from Conus princeps Displays a Novel Molecular Target

by Johanna Bernáldez, Samanta Jiménez, Luis Javier González, Jesús Noda Ferro, Enrique Soto, Emilio Salceda, Daniela Chávez, Manuel B. Aguilar and Alexei Licea-Navarro

Toxins 2016, 8(2), 39; doi:10.3390/toxins8020039

Received: 3 November 2015 / Revised: 22 January 2016 / Accepted: 25 January 2016 / Published: 5 February 2016

Viewed by 926 | PDF Full-text (2559 KB) | HTML Full-text | XML Full-text

Abstract

A novel conotoxin, named as PiVIIA, was isolated from the venom of Conus princeps, a marine predatory cone snail collected in the Pacific Southern Coast of Mexico. Chymotryptic digest of the S-alkylated peptide in combination with liquid chromatography coupled to tandem mass

[...] Read more.

A novel conotoxin, named as PiVIIA, was isolated from the venom of Conus princeps, a marine predatory cone snail collected in the Pacific Southern Coast of Mexico. Chymotryptic digest of the S-alkylated peptide in combination with liquid chromatography coupled to tandem mass spectrometry, were used to define the sequencing of this peptide. Eleven N-terminal amino acids were verified by automated Edman degradation. PiVIIA is a 25-mer peptide (CDAOTHYCTNYWγCCSGYCγHSHCW) with six cysteine residues forming three disulphide bonds, a hydroxyproline (O) and two gamma carboxyglutamic acid (γ) residues. Based on the arrangement of six Cys residues (C-C-CC-C-C), this conotoxin might belong to the O2-superfamily. Moreover, PiVIIA has a conserved motif (-γCCS-) that characterizes γ-conotoxins from molluscivorous Conus. Peptide PiVIIA has 45% sequence identity with γ-PnVIIA—the prototype of this family. Biological activity of PiVIIA was assessed by voltage-clamp recording in rat dorsal root ganglion neurons. Perfusion of PiVIIA in the µM range produces a significant increase in the Ca²⁺ currents, without significantly modifying the Na⁺, K⁺ or proton-gated acid sensing ionic currents. These results indicate that PiVIIA is a new conotoxin whose activity deserves further studies to define its potential use as a positive modulator of neuronal activity. Full article

(This article belongs to the collection Marine and Freshwater Toxins)

Open AccessArticle Biodistribution, Stability, and Blood Distribution of the Cell Penetrating Peptide Maurocalcine in Mice

by Pascale Perret, Mitra Ahmadi, Laurent Riou, Sandrine Bacot, Julien Pecher, Cathy Poillot, Alexis Broisat, Catherine Ghezzi and Michel De Waard

Int. J. Mol. Sci. 2015, 16(11), 27730-27740; doi:10.3390/ijms161126054

Received: 27 August 2015 / Revised: 22 October 2015 / Accepted: 22 October 2015 / Published: 19 November 2015

Viewed by 1042 | PDF Full-text (2177 KB) | HTML Full-text | XML Full-text

Abstract

Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make

[...] Read more.

Maurocalcine (MCa) is the first natural cell penetrating peptide to be discovered in animal venom. In addition to the fact that it represents a potent vector for the cell penetration of structurally diverse therapeutic compounds, MCa also displays several distinguishing features that make it a potential peptide of choice for clinical and biotechnological applications. The aim of the present study was to gain new information about the properties of MCa in vivo in order to delineate the future potential applications of this vector. For this purpose, two analogues of this peptide with (Tyr-MCa) and without (Lin-Tyr-MCa) disulfide bridges were synthesized, radiolabeled with ¹²⁵I, and their in vitro stabilities were first evaluated in mouse blood. The results indicated that ¹²⁵I-Tyr-MCa was stable in vitro and that the disulfide bridges conferred a competitive advantage for the stability of peptide. Following in vivo injection in mice, ¹²⁵I-Tyr-MCa targeted peripheral organs with interesting quantitative differences and the main route of peptide elimination was renal. Full article

(This article belongs to the Special Issue Cell-Penetrating Peptides)

Open AccessCommunication Developing a Dissociative Nanocontainer for Peptide Drug Delivery

by Patrick Kelly, Prachi Anand, Alexander Uvaydov, Srinivas Chakravartula, Chhime Sherpa, Elena Pires, Alison O’Neil, Trevor Douglas and Mandë Holford

Int. J. Environ. Res. Public Health 2015, 12(10), 12543-12555; doi:10.3390/ijerph121012543

Received: 17 August 2015 / Revised: 23 September 2015 / Accepted: 28 September 2015 / Published: 9 October 2015

Cited by 6 | Viewed by 1070 | PDF Full-text (1745 KB) | HTML Full-text | XML Full-text

Abstract

The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is

[...] Read more.

The potency, selectivity, and decreased side effects of bioactive peptides have propelled these agents to the forefront of pharmacological research. Peptides are especially promising for the treatment of neurological disorders and pain. However, delivery of peptide therapeutics often requires invasive techniques, which is a major obstacle to their widespread application. We have developed a tailored peptide drug delivery system in which the viral capsid of P22 bacteriophage is modified to serve as a tunable nanocontainer for the packaging and controlled release of bioactive peptides. Recent efforts have demonstrated that P22 nanocontainers can effectively encapsulate analgesic peptides and translocate them across blood-brain-barrier (BBB) models. However, release of encapsulated peptides at their target site remains a challenge. Here a Ring Opening Metathesis Polymerization (ROMP) reaction is applied to trigger P22 nanocontainer disassembly under physiological conditions. Specifically, the ROMP substrate norbornene (5-Norbornene-2-carboxylic acid) is conjugated to the exterior of a loaded P22 nanocontainer and Grubbs II Catalyst is used to trigger the polymerization reaction leading to nanocontainer disassembly. Our results demonstrate initial attempts to characterize the ROMP-triggered release of cargo peptides from P22 nanocontainers. This work provides proof-of-concept for the construction of a triggerable peptide drug delivery system using viral nanocontainers. Full article

(This article belongs to the Special Issue Nanomaterials-Based New Techniques, New Drugs, and Antibacterial Reagents)

► Figures

Open AccessAddendum Addendum: Qian, C.; Fang, Q.; Wang, L.; Ye, G.Y. Molecular Cloning and Functional Studies of Two Kazal-Type Serine Protease Inhibitors Specifically Expressed by Nasonia vitripennis Venom Apparatus. Toxins 2015, 7, 2888–2905

by Cen Qian, Qi Fang, Lei Wang and Gong-Yin Ye

Toxins 2015, 7(9), 3636; doi:10.3390/toxins7093636

Received: 1 September 2015 / Accepted: 6 September 2015 / Published: 11 September 2015

Viewed by 596 | PDF Full-text (257 KB) | HTML Full-text | XML Full-text

Abstract

This research was supported by grants from the National Program on Key Basic Research Projects (973 Program, 2013CB127600), the National Natural Science Foundation of China (Grant Nos. 31272098, 31472038, 31402018), the Research Fund for the Doctoral Program of Higher Education of China (Grant

[...] Read more.

This research was supported by grants from the National Program on Key Basic Research Projects (973 Program, 2013CB127600), the National Natural Science Foundation of China (Grant Nos. 31272098, 31472038, 31402018), the Research Fund for the Doctoral Program of Higher Education of China (Grant Number 2012010113004), the National Science Fund for Innovative Research Groups of Biological Control (Grant No. 31321063), the Zhejiang Provincial Natural Science Foundation of China (Grant Number Y14C140006) and the Fundamental Research Funds for the Central Universities (Grant Number 2014FZA6014). [...] Full article

Open AccessArticle Development of Plate Reader and On-Line Microfluidic Screening to Identify Ligands of the 5-Hydroxytryptamine Binding Protein in Venoms

by Reka A. Otvos, Janaki Krishnamoorthy Iyer, René van Elk, Chris Ulens, Wilfried M. A. Niessen, Govert W. Somsen, R. Manjunatha Kini, August B. Smit and Jeroen Kool

Toxins 2015, 7(7), 2336-2353; doi:10.3390/toxins7072336

Received: 27 March 2015 / Revised: 6 May 2015 / Accepted: 16 June 2015 / Published: 24 June 2015

Abstract

The 5-HT₃ receptor is a ligand-gated ion channel, which is expressed in the nervous system. Its antagonists are used clinically for treatment of postoperative- and radiotherapy-induced emesis and irritable bowel syndrome. In order to better understand the structure and function of the

[...] Read more.

The 5-HT₃ receptor is a ligand-gated ion channel, which is expressed in the nervous system. Its antagonists are used clinically for treatment of postoperative- and radiotherapy-induced emesis and irritable bowel syndrome. In order to better understand the structure and function of the 5-HT₃ receptor, and to allow for compound screening at this receptor, recently a serotonin binding protein (5HTBP) was engineered with the Acetylcholine Binding Protein as template. In this study, a fluorescence enhancement assay for 5HTBP ligands was developed in plate-reader format and subsequently used in an on-line microfluidic format. Both assay types were validated using an existing radioligand binding assay. The on-line microfluidic assay was coupled to HPLC via a post-column split which allowed parallel coupling to a mass spectrometer to collect MS data. This high-resolution screening (HRS) system is well suitable for compound mixture analysis. As a proof of principle, the venoms of Dendroapsis polylepis, Pseudonaja affinis and Pseudonaja inframacula snakes were screened and the accurate masses of the found bioactives were established. To demonstrate the subsequent workflow towards structural identification of bioactive proteins and peptides, the partial amino acid sequence of one of the bioactives from the Pseudonaja affinis venom was determined using a bottom-up proteomics approach. Full article

(This article belongs to the Special Issue Selected Papers from the 5th Venoms to Drugs Meeting)

Open AccessReview Sphingomyelinase D/Ceramide 1-Phosphate in Cell Survival and Inflammation

by Io-Guané Rivera, Marta Ordoñez, Natalia Presa, Ana Gomez-Larrauri, Jorge Simón, Miguel Trueba and Antonio Gomez-Muñoz

Toxins 2015, 7(5), 1457-1466; doi:10.3390/toxins7051457

Received: 30 March 2015 / Revised: 20 April 2015 / Accepted: 22 April 2015 / Published: 29 April 2015

Cited by 14 | Viewed by 1443 | PDF Full-text (234 KB) | HTML Full-text | XML Full-text

Abstract

Sphingolipids are major constituents of biological membranes of eukaryotic cells. Many studies have shown that sphingomyelin (SM) is a major phospholipid in cell bilayers and is mainly localized to the plasma membrane of cells, where it serves both as a building block for

[...] Read more.

Sphingolipids are major constituents of biological membranes of eukaryotic cells. Many studies have shown that sphingomyelin (SM) is a major phospholipid in cell bilayers and is mainly localized to the plasma membrane of cells, where it serves both as a building block for cell architecture and as a precursor of bioactive sphingolipids. In particular, upregulation of (C-type) sphingomyelinases will produce ceramide, which regulates many physiological functions including apoptosis, senescence, or cell differentiation. Interestingly, the venom of some arthropodes including spiders of the genus Loxosceles, or the toxins of some bacteria such as Corynebacterium tuberculosis, or Vibrio damsela possess high levels of D-type sphingomyelinase (SMase D). This enzyme catalyzes the hydrolysis of SM to yield ceramide 1-phosphate (C1P), which promotes cell growth and survival and is a potent pro-inflammatory agent in different cell types. In particular, C1P stimulates cytosolic phospholipase A2 leading to arachidonic acid release and the subsequent formation of eicosanoids, actions that are all associated to the promotion of inflammation. In addition, C1P potently stimulates macrophage migration, which has also been associated to inflammatory responses. Interestingly, this action required the interaction of C1P with a specific plasma membrane receptor, whereas accumulation of intracellular C1P failed to stimulate chemotaxis. The C1P receptor is coupled to Gi proteins and activates of the PI3K/Akt and MEK/ERK1-2 pathways upon ligation with C1P. The proposed review will address novel aspects on the control of inflammatory responses by C1P and will highlight the molecular mechanisms whereby C1P exerts these actions. Full article

(This article belongs to the Special Issue G-Protein Coupled Receptors as mediators of Toxin effects)

Open AccessReview Three Valuable Peptides from Bee and Wasp Venoms for Therapeutic and Biotechnological Use: Melittin, Apamin and Mastoparan

by Miguel Moreno and Ernest Giralt

Toxins 2015, 7(4), 1126-1150; doi:10.3390/toxins7041126

Received: 4 February 2015 / Revised: 18 March 2015 / Accepted: 25 March 2015 / Published: 1 April 2015

Cited by 37 | Viewed by 2246 | PDF Full-text (261 KB) | HTML Full-text | XML Full-text

Abstract

While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms are now being studied with the aim to design and develop

[...] Read more.

While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms are now being studied with the aim to design and develop new therapeutic drugs. Far from evaluating the extensive number of monographs, journals and books related to bee and wasp venoms and the therapeutic effect of these toxins in numerous diseases, the following review focuses on the three most characterized peptides, namely melittin, apamin, and mastoparan. Here, we update information related to these compounds from the perspective of applied science and discuss their potential therapeutic and biotechnological applications in biomedicine. Full article

(This article belongs to the Special Issue Bee and Wasp Venoms: Biological Characteristics and Therapeutic Application) Printed Edition available

Open AccessReview Chlorotoxin: A Helpful Natural Scorpion Peptide to Diagnose Glioma and Fight Tumor Invasion

by Lucie Dardevet, Dipti Rani, Tarek Abd El Aziz, Ingrid Bazin, Jean-Marc Sabatier, Mahmoud Fadl, Elisabeth Brambilla and Michel De Waard

Toxins 2015, 7(4), 1079-1101; doi:10.3390/toxins7041079

Received: 12 November 2014 / Revised: 22 December 2014 / Accepted: 20 February 2015 / Published: 27 March 2015

Cited by 17 | Viewed by 2147 | PDF Full-text (730 KB) | HTML Full-text | XML Full-text

Abstract

Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties

[...] Read more.

Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma-specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin. Full article

(This article belongs to the Special Issue Ion Channel Neurotoxins)

Open AccessArticle The Anti-Cancer Potency and Mechanism of a Novel Tumor-Activated Fused Toxin, DLM

by Dejun Sun, Miaonan Sun, Wenhe Zhu, Zhiding Wang, Yuefei Li and Jie Ma

Toxins 2015, 7(2), 423-438; doi:10.3390/toxins7020423

Received: 25 July 2014 / Revised: 4 December 2014 / Accepted: 21 January 2015 / Published: 4 February 2015

Abstract

Melittin, which acts as a membrane-disrupting lytic peptide, is not only cytotoxic to tumors, but also vital to normal cells. Melittin had low toxicity when coupled with target peptides. Despite significant research development with the fused toxin, a new fused toxin is needed

[...] Read more.

Melittin, which acts as a membrane-disrupting lytic peptide, is not only cytotoxic to tumors, but also vital to normal cells. Melittin had low toxicity when coupled with target peptides. Despite significant research development with the fused toxin, a new fused toxin is needed which has a cleavable linker such that the fused toxin can release melittin after protease cleavage on the tumor cell surface. We describe a novel fused toxin, composed of disintegrin, uPA (urokinase-type plasminogen activator)-cleavable linker, and melittin. Disintegrin is a single strand peptide (73 aa) isolated from Gloydius Ussuriensis venom. The RGD (Arg-Gly-Asp) site of disintegrin dominates its interaction with integrins on the surface of the tumor cells. uPA is over-expressed and plays an important role in tumor cell invasiveness and metastatic progression. The DLM (disintegrin-linker-melittin) linker is uPA-cleavable, enabling DLM to release melittin. We compared binding activity of our synthesized disintegrin with native disintegrin and report that DLM had less binding activity than the native form. uPA-cleavage was evaluated in vitro and the uPA-cleavable linker released melittin. Treating tumors expressing uPA with DLM enhanced tumor cell killing as well as reduced toxicity to erythrocytes and other non-cancerous normal cells. The mechanism behind DLM tumor cell killing was tested using a DNA ladder assay, fluorescent microscopy, flow cytometry, and transmission electron microscopy. Data revealed tumor cell necrosis as the mechanism of cell death, and the fused DLM toxin with an uPA-cleavable linker enhanced tumor selectivity and killing ability. Full article

(This article belongs to the Section Animal Venoms)

Open AccessReview Conotoxin Gene Superfamilies

by Samuel D. Robinson and Raymond S. Norton

Mar. Drugs 2014, 12(12), 6058-6101; doi:10.3390/md12126058

Received: 28 October 2014 / Revised: 29 November 2014 / Accepted: 4 December 2014 / Published: 17 December 2014

Cited by 30 | Viewed by 1661 | PDF Full-text (2366 KB) | HTML Full-text | XML Full-text

Abstract

Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research

[...] Read more.

Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing. Full article

(This article belongs to the Special Issue Marine Peptides and Their Mimetics)

► Figures

Open AccessArticle The Activation Effect of Hainantoxin-I, a Peptide Toxin from the Chinese Spider, Ornithoctonus hainana, on Intermediate-Conductance Ca²⁺-Activated K⁺ Channels

by Pengfei Huang, Yiya Zhang, Xinyi Chen, Li Zhu, Dazhong Yin, Xiongzhi Zeng and Songping Liang

Toxins 2014, 6(8), 2568-2579; doi:10.3390/toxins6082568

Received: 26 May 2014 / Revised: 28 July 2014 / Accepted: 14 August 2014 / Published: 21 August 2014

Viewed by 1386 | PDF Full-text (749 KB) | HTML Full-text | XML Full-text

Abstract

Intermediate-conductance Ca²⁺-activated K⁺ (IK) channels are calcium/calmodulin-regulated voltage-independent K⁺ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to

[...] Read more.

Intermediate-conductance Ca²⁺-activated K⁺ (IK) channels are calcium/calmodulin-regulated voltage-independent K⁺ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na⁺ and Ca²⁺ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K⁺ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

Open AccessArticle Synthesis and Analgesic Effects of μ-TRTX-Hhn1b on Models of Inflammatory and Neuropathic Pain

by Yu Liu, Jianguang Tang, Yunxiao Zhang, Xiaohong Xun, Dongfang Tang, Dezheng Peng, Jianming Yi, Zhonghua Liu and Xiaoliu Shi

Toxins 2014, 6(8), 2363-2378; doi:10.3390/toxins6082363

Received: 28 March 2014 / Revised: 17 July 2014 / Accepted: 18 July 2014 / Published: 13 August 2014

Cited by 3 | Viewed by 1640 | PDF Full-text (1126 KB) | HTML Full-text | XML Full-text

Abstract

μ-TRTX-Hhn1b (HNTX-IV) is a 35-amino acid peptide isolated from the venom of the spider, Ornithoctonus hainana. It inhibits voltage-gated sodium channel Nav1.7, which has been considered as a therapeutic target for pain. The goal of the present study is to elucidate the

[...] Read more.

μ-TRTX-Hhn1b (HNTX-IV) is a 35-amino acid peptide isolated from the venom of the spider, Ornithoctonus hainana. It inhibits voltage-gated sodium channel Nav1.7, which has been considered as a therapeutic target for pain. The goal of the present study is to elucidate the analgesic effects of synthetic μ-TRTX-Hhn1b on animal models of pain. The peptide was first synthesized and then successfully refolded/oxidized. The synthetic peptide had the same inhibitory effect on human Nav1.7 current transiently expressed in HEK 293 cells as the native toxin. Furthermore, the analgesic potentials of the synthetic peptide were examined on models of inflammatory pain and neuropathic pain. μ-TRTX-Hhn1b produced an efficient reversal of acute nociceptive pain in the abdominal constriction model, and significantly reduced the pain scores over the 40-min period in the formalin model. The efficiency of μ-TRTX-Hhn1b on both models was equivalent to that of morphine. In the spinal nerve model, the reversal effect of μ-TRTX-Hhn1b on allodynia was longer and higher than mexiletine. These results demonstrated that μ-TRTX-Hhn1b efficiently alleviated acute inflammatory pain and chronic neuropathic pain in animals and provided an attractive template for further clinical analgesic drug design. Full article

(This article belongs to the Special Issue Ion Channel Neurotoxins)

Open AccessReview Cytotoxic and Cytolytic Cnidarian Venoms. A Review on Health Implications and Possible Therapeutic Applications

by Gian Luigi Mariottini and Luigi Pane

Toxins 2014, 6(1), 108-151; doi:10.3390/toxins6010108

Received: 5 November 2013 / Revised: 11 December 2013 / Accepted: 13 December 2013 / Published: 27 December 2013

Cited by 21 | Viewed by 2084 | PDF Full-text (366 KB) | HTML Full-text | XML Full-text

Abstract

The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested

[...] Read more.

The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested in order to evaluate some fundamental parameters, such as the activity on cell survival, functioning and metabolism, and to improve the knowledge about the mechanisms of action of these compounds. In agreement with the modern tendency aimed to avoid the utilization of living animals in the experiments and to substitute them with in vitro systems, established cell lines or primary cultures have been employed to test cnidarian extracts or derivatives. Several cnidarian venoms have been found to have cytotoxic properties and have been also shown to cause hemolytic effects. Some studied substances have been shown to affect tumour cells and microorganisms, so making cnidarian extracts particularly interesting for their possible therapeutic employment. The review aims to emphasize the up-to-date knowledge about this subject taking in consideration the importance of such venoms in human pathology, the health implications and the possible therapeutic application of these natural compounds. Full article

(This article belongs to the collection Marine and Freshwater Toxins)

Open AccessComment The Deciphered Genome of Mesobuthus martensii Uncovers the Resistance Mysteries of Scorpion to Its Own Venom and Toxins at the Ion Channel Level

by Nicolas Andreotti and Jean-Marc Sabatier

Toxins 2013, 5(11), 2209-2211; doi:10.3390/toxins5112209

Received: 4 November 2013 / Accepted: 13 November 2013 / Published: 18 November 2013

Cited by 2 | Viewed by 1250 | PDF Full-text (145 KB) | HTML Full-text | XML Full-text

Abstract Scorpions are amongst the most ancient arthropods, as the oldest fossils were dated from the late silurian (Proscorpius osborni, 418 million years B.P.) Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle NMR Solution Structure of a Chymotrypsin Inhibitor from the Taiwan Cobra Naja naja atra

by Yi-Jan Lin, Teppei Ikeya, Peter Güntert and Long-Sen Chang

Molecules 2013, 18(8), 8906-8918; doi:10.3390/molecules18088906

Received: 14 June 2013 / Revised: 19 July 2013 / Accepted: 22 July 2013 / Published: 26 July 2013

Cited by 2 | Viewed by 2236 | PDF Full-text (1686 KB) | HTML Full-text | XML Full-text

Abstract

The Taiwan cobra (Naja naja atra) chymotrypsin inhibitor (NACI) consists of 57 amino acids and is related to other Kunitz-type inhibitors such as bovine pancreatic trypsin inhibitor (BPTI) and Bungarus fasciatus fraction IX (BF9), another chymotrypsin inhibitor. Here we present the

[...] Read more.

The Taiwan cobra (Naja naja atra) chymotrypsin inhibitor (NACI) consists of 57 amino acids and is related to other Kunitz-type inhibitors such as bovine pancreatic trypsin inhibitor (BPTI) and Bungarus fasciatus fraction IX (BF9), another chymotrypsin inhibitor. Here we present the solution structure of NACI. We determined the NMR structure of NACI with a root-mean-square deviation of 0.37 Å for the backbone atoms and 0.73 Å for the heavy atoms on the basis of 1,075 upper distance limits derived from NOE peaks measured in its NOESY spectra. To investigate the structural characteristics of NACI, we compared the three-dimensional structure of NACI with BPTI and BF9. The structure of the NACI protein comprises one 3₁₀-helix, one α-helix and one double-stranded antiparallel β-sheet, which is comparable with the secondary structures in BPTI and BF9. The RMSD value between the mean structures is 1.09 Å between NACI and BPTI and 1.27 Å between NACI and BF9. In addition to similar secondary and tertiary structure, NACI might possess similar types of protein conformational fluctuations as reported in BPTI, such as Cys14–Cys38 disulfide bond isomerization, based on line broadening of resonances from residues which are mainly confined to a region around the Cys14–Cys38 disulfide bond. Full article

(This article belongs to the Special Issue NMR of Proteins and Small Biomolecules)

► Figures

Figure 1

Open AccessReview Strategies for the Development of Conotoxins as New Therapeutic Leads

by Ryan M. Brady, Jonathan B. Baell and Raymond S. Norton

Mar. Drugs 2013, 11(7), 2293-2313; doi:10.3390/md11072293

Received: 14 April 2013 / Revised: 27 May 2013 / Accepted: 6 June 2013 / Published: 28 June 2013

Cited by 13 | Viewed by 2135 | PDF Full-text (659 KB) | HTML Full-text | XML Full-text

Abstract

Peptide toxins typically bind to their target ion channels or receptors with high potency and selectivity, making them attractive leads for therapeutic development. In some cases the native peptide as it is found in the venom from which it originates can be used

[...] Read more.

Peptide toxins typically bind to their target ion channels or receptors with high potency and selectivity, making them attractive leads for therapeutic development. In some cases the native peptide as it is found in the venom from which it originates can be used directly, but in many instances it is desirable to truncate and/or stabilize the peptide to improve its therapeutic properties. A complementary strategy is to display the key residues that make up the pharmacophore of the peptide toxin on a non-peptidic scaffold, thereby creating a peptidomimetic. This review exemplifies these approaches with peptide toxins from marine organisms, with a particular focus on conotoxins. Full article

(This article belongs to the Special Issue Marine Peptides and Their Mimetics)

► Figures

Open AccessArticle A Conus regularis Conotoxin with a Novel Eight-Cysteine Framework Inhibits Ca_V2.2 Channels and Displays an Anti-Nociceptive Activity

by Johanna Bernáldez, Sergio A. Román-González, Oscar Martínez, Samanta Jiménez, Oscar Vivas, Isabel Arenas, Gerardo Corzo, Roberto Arreguín, David E. García, Lourival D. Possani and Alexei Licea

Mar. Drugs 2013, 11(4), 1188-1202; doi:10.3390/md11041188

Received: 7 February 2013 / Revised: 5 March 2013 / Accepted: 18 March 2013 / Published: 8 April 2013

Cited by 9 | Viewed by 2796 | PDF Full-text (597 KB) | HTML Full-text | XML Full-text

Abstract

A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40

[...] Read more.

A novel peptide, RsXXIVA, was isolated from the venom duct of Conus regularis, a worm-hunting species collected in the Sea of Cortez, México. Its primary structure was determined by mass spectrometry and confirmed by automated Edman degradation. This conotoxin contains 40 amino acids and exhibits a novel arrangement of eight cysteine residues (C-C-C-C-CC-CC). Surprisingly, two loops of the novel peptide are highly identical to the amino acids sequence of ω-MVIIA. The total length and disulfide pairing of both peptides are quite different, although the two most important residues for the described function of ω-MVIIA (Lys2 and Tyr13) are also present in the peptide reported here. Electrophysiological analysis using superior cervical ganglion (SCG) neurons indicates that RsXXIVA inhibits Ca_V2.2 channel current in a dose-dependent manner with an EC₅₀ of 2.8 μM, whose effect is partially reversed after washing. Furthermore, RsXXIVA was tested in hot-plate assays to measure the potential anti-nociceptive effect to an acute thermal stimulus, showing an analgesic effect in acute thermal pain at 30 and 45 min post-injection. Also, the toxin shows an anti-nociceptive effect in a formalin chronic pain test. However, the low affinity for Ca_V2.2 suggests that the primary target of the peptide could be different from that of ω-MVIIA. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

Open AccessReview Conotoxins that Confer Therapeutic Possibilities

by Magbubah Essack, Vladimir B. Bajic and John A. C. Archer

Mar. Drugs 2012, 10(6), 1244-1265; doi:10.3390/md10061244

Received: 6 February 2012 / Revised: 24 April 2012 / Accepted: 24 May 2012 / Published: 4 June 2012

Abstract

Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an

[...] Read more.

Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt^®; Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring ω-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred. Full article

► Figures

Open AccessReview Disintegrins from Hematophagous Sources

by Teresa C. F. Assumpcao, José M. C. Ribeiro and Ivo M. B. Francischetti

Toxins 2012, 4(5), 296-322; doi:10.3390/toxins4050296

Received: 23 February 2012 / Revised: 12 April 2012 / Accepted: 13 April 2012 / Published: 26 April 2012

Abstract

Bloodsucking arthropods are a rich source of salivary molecules (sialogenins) which inhibit platelet aggregation, neutrophil function and angiogenesis. Here we review the literature on salivary disintegrins and their targets. Disintegrins were first discovered in snake venoms, and were instrumental in our understanding of

[...] Read more.

Bloodsucking arthropods are a rich source of salivary molecules (sialogenins) which inhibit platelet aggregation, neutrophil function and angiogenesis. Here we review the literature on salivary disintegrins and their targets. Disintegrins were first discovered in snake venoms, and were instrumental in our understanding of integrin function and also for the development of anti-thrombotic drugs. In hematophagous animals, most disintegrins described so far have been discovered in the salivary gland of ticks and leeches. A limited number have also been found in hookworms and horseflies, and none identified in mosquitoes or sand flies. The vast majority of salivary disintegrins reported display a RGD motif and were described as platelet aggregation inhibitors, and few others as negative modulator of neutrophil or endothelial cell functions. This notably low number of reported disintegrins is certainly an underestimation of the actual complexity of this family of proteins in hematophagous secretions. Therefore an algorithm was created in order to identify the tripeptide motifs RGD, KGD, VGD, MLD, KTS, RTS, WGD, or RED (flanked by cysteines) in sialogenins deposited in GenBank database. The search included sequences from various blood-sucking animals such as ticks (e.g., Ixodes sp., Argas sp., Rhipicephalus sp., Amblyomma sp.), tabanids (e.g., Tabanus sp.), bugs (e.g., Triatoma sp., Rhodnius prolixus), mosquitoes (e.g., Anopheles sp., Aedes sp., Culex sp.), sand flies (e.g., Lutzomyia sp., Phlebotomus sp.), leeches (e.g., Macrobdella sp., Placobdella sp.) and worms (e.g., Ancylostoma sp.). This approach allowed the identification of a remarkably high number of novel putative sialogenins with tripeptide motifs typical of disintegrins (>450 sequences) whose biological activity remains to be verified. This database is accessible online as a hyperlinked worksheet and displays biochemical, taxonomic, and gene ontology aspects for each putative disintegrin. It is also freely available for download (right click with the mouse) at links http://exon.niaid.nih.gov/transcriptome/RGD/RGD-Peps-WEB.xlsx (web version) and http://exon.niaid.nih.gov/transcriptome/RGD/RGD-sialogenins.zip (stand alone version). Full article

(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)

Open AccessArticle Molecular Conversion of Muscarinic Acetylcholine Receptor M₅ to Muscarinic Toxin 7 (MT7)-Binding Protein

by Sergio Rondinelli, Katja Näreoja and Johnny Näsman

Toxins 2011, 3(11), 1393-1404; doi:10.3390/toxins3111393

Received: 19 September 2011 / Revised: 11 October 2011 / Accepted: 3 November 2011 / Published: 11 November 2011

Cited by 2 | Viewed by 1955 | PDF Full-text (971 KB) | HTML Full-text | XML Full-text

Abstract

Muscarinic toxin 7 (MT7) is a mamba venom peptide that binds selectively to the M₁ muscarinic acetylcholine receptor. We have previously shown that the second (ECL2) and third (ECL3) extracellular loops of the M₁ receptor are critically involved in binding the

[...] Read more.

Muscarinic toxin 7 (MT7) is a mamba venom peptide that binds selectively to the M₁ muscarinic acetylcholine receptor. We have previously shown that the second (ECL2) and third (ECL3) extracellular loops of the M₁ receptor are critically involved in binding the peptide. In this study we used a mutagenesis approach on the M₅ subtype of the receptor family to find out if this possesses a similar structural architecture in terms of toxin binding as the M₁ receptor. An M₅ receptor construct (M₅-E¹⁷⁵Y¹⁸⁴E⁴⁷⁴), mutated at the formerly deciphered critical residues on ECL2 and 3, gained the ability to bind MT7, but with rather low affinity as determined in a functional assay (apparent K_i = 24 nM; apparent K_i for M₁ = 0.5 nM). After screening for different domains and residues, we found a specific residue (P¹⁷⁹ to L in M₅) in the middle portion of ECL2 that was necessary for high affinity binding of MT7 (M₅-EL¹⁷⁹YE, apparent K_i = 0.5 nM). Mutation of P¹⁷⁹ to A confirmed a role for the leucine side chain in the binding of MT7. Together the results reveal new binding interactions between receptors and the MT7 peptide and strengthen the hypothesis that ECL2 sequence is of utmost importance for MT binding to muscarinic receptors. Full article

(This article belongs to the Special Issue Snake Venoms)

Open AccessArticle Bioactive Indole Derivatives from the South Pacific Marine Sponges Rhopaloeides odorabile and Hyrtios sp.

by Arlette Longeon, Brent R. Copp, Elodie Quévrain, Mélanie Roué, Betty Kientz, Thierry Cresteil, Sylvain Petek, Cécile Debitus and Marie-Lise Bourguet-Kondracki

Mar. Drugs 2011, 9(5), 879-888; doi:10.3390/md9050879

Received: 13 April 2011 / Revised: 16 May 2011 / Accepted: 17 May 2011 / Published: 24 May 2011

Cited by 21 | Viewed by 3979 | PDF Full-text (339 KB) | HTML Full-text | XML Full-text

Abstract

Indole derivatives including bromoindoles have been isolated from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. Their structures were established through analysis of mass spectra and 1D and 2D NMR spectroscopic data. Their potential inhibitory phospholipase A₂ (PLA₂),

[...] Read more.

Indole derivatives including bromoindoles have been isolated from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. Their structures were established through analysis of mass spectra and 1D and 2D NMR spectroscopic data. Their potential inhibitory phospholipase A₂ (PLA₂), antioxidant and cytotoxic activities were evaluated. The new derivative 5,6-dibromo-l-hypaphorine (9) isolated from Hyrtios sp. revealed a weak bee venom PLA₂ inhibition (IC₅₀ 0.2 mM) and a significant antioxidant activity with an Oxygen Radical Absorbance Capacity (ORAC) value of 0.22. The sesquiterpene aureol (4), also isolated from Hyrtios sp., showed the most potent antioxidant activity with an ORAC value of 0.29. Full article

Open AccessArticle Alpha-Latrotoxin Rescues SNAP-25 from BoNT/A-Mediated Proteolysis in Embryonic Stem Cell-Derived Neurons

by Mariano Mesngon and Patrick McNutt

Toxins 2011, 3(5), 489-503; doi:10.3390/toxins3050489

Received: 11 March 2011 / Revised: 22 April 2011 / Accepted: 29 April 2011 / Published: 13 May 2011

Cited by 13 | Viewed by 3598 | PDF Full-text (501 KB) | HTML Full-text | XML Full-text

Abstract

The botulinum neurotoxins (BoNTs) exhibit zinc-dependent proteolytic activity against members of the core synaptic membrane fusion complex, preventing neurotransmitter release and resulting in neuromuscular paralysis. No pharmacologic therapies have been identified that clinically relieve botulinum poisoning. The black widow spider venom α-latrotoxin (LTX)

[...] Read more.

The botulinum neurotoxins (BoNTs) exhibit zinc-dependent proteolytic activity against members of the core synaptic membrane fusion complex, preventing neurotransmitter release and resulting in neuromuscular paralysis. No pharmacologic therapies have been identified that clinically relieve botulinum poisoning. The black widow spider venom α-latrotoxin (LTX) has the potential to attenuate the severity or duration of BoNT-induced paralysis in neurons via the induction of synaptic degeneration and remodeling. The potential for LTX to antagonize botulinum poisoning was evaluated in embryonic stem cell-derived neurons (ESNs), using a novel screening assay designed around the kinetics of BoNT/A activation. Exposure of ESNs to 400 pM LTX for 6.5 or 13 min resulted in the nearly complete restoration of uncleaved SNAP-25 within 48 h, whereas treatment with 60 mM K⁺ had no effect. Time-lapse imaging demonstrated that LTX treatment caused a profound increase in Ca²⁺ influx and evidence of excitotoxicity, though ESNs remained viable 48 h after LTX treatment. This is the first instance of a cell-based treatment that has shown the ability to eliminate BoNT activity. These data suggest that LTX treatment may provide the basis for a new class of therapeutic approach to BoNT intoxication and may contribute to an improved understanding of long-term mechanisms of BoNT intoxication and recovery. They further demonstrate that ESNs are a novel, responsive and biologically relevant model for LTX research and BoNT therapeutic drug discovery. Full article

(This article belongs to the Special Issue Development of Botulinum Toxin Drugs)

Open AccessReview Proteases as Insecticidal Agents

by Robert L. Harrison and Bryony C. Bonning

Toxins 2010, 2(5), 935-953; doi:10.3390/toxins2050935

Received: 12 April 2010 / Revised: 26 April 2010 / Accepted: 30 April 2010 / Published: 5 May 2010

Cited by 26 | Viewed by 6271 | PDF Full-text (300 KB) | HTML Full-text | XML Full-text

Abstract

Proteases from a variety of sources (viruses, bacteria, fungi, plants, and insects) have toxicity towards insects. Some of these insecticidal proteases evolved as venom components, herbivore resistance factors, or microbial pathogenicity factors, while other proteases play roles in insect development or digestion, but

[...] Read more.

Proteases from a variety of sources (viruses, bacteria, fungi, plants, and insects) have toxicity towards insects. Some of these insecticidal proteases evolved as venom components, herbivore resistance factors, or microbial pathogenicity factors, while other proteases play roles in insect development or digestion, but exert an insecticidal effect when over-expressed from genetically engineered plants or microbial pathogens. Many of these proteases are cysteine proteases, although insect-toxic metalloproteases and serine proteases have also been examined. The sites of protease toxic activity range from the insect midgut to the hemocoel (body cavity) to the cuticle. This review discusses these insecticidal proteases along with their evaluation and use as potential pesticides. Full article

(This article belongs to the Special Issue Protein Toxins as Proteases)

► Figures

Open AccessReview Fibrolase: Trials and Tribulations

by Francis S. Markland and Steve Swenson

Toxins 2010, 2(4), 793-808; doi:10.3390/toxins2040793

Received: 11 March 2010 / Revised: 31 March 2010 / Accepted: 19 April 2010 / Published: 20 April 2010

Cited by 10 | Viewed by 4571 | PDF Full-text (285 KB) | HTML Full-text | XML Full-text

Abstract

Fibrolase is the fibrinolytic enzyme isolated from Agkistrodon contortrix contortrix (southern copperhead snake) venom. The enzyme was purified by a three-step HPLC procedure and was shown to be homogeneous by standard criteria including reverse phase HPLC, molecular sieve chromatography and SDS-PAGE. The purified

[...] Read more.

Fibrolase is the fibrinolytic enzyme isolated from Agkistrodon contortrix contortrix (southern copperhead snake) venom. The enzyme was purified by a three-step HPLC procedure and was shown to be homogeneous by standard criteria including reverse phase HPLC, molecular sieve chromatography and SDS-PAGE. The purified enzyme is a zinc metalloproteinase containing one mole of zinc. It is composed of 203 amino acids with a blocked amino-terminus due to cyclization of the terminal Gln residue. Fibrolase shares a significant degree of homology with enzymes of the reprolysin sub-family of metalloproteinases including an active site homology of close to 100%; it is rapidly inhibited by chelating agents such as EDTA, and by alpha2-macroglobulin (α2M). The enzyme is a direct-acting thrombolytic agent and does not rely on plasminogen for clot dissolution. Fibrolase rapidly cleaves the A(α)-chain of fibrinogen and the B(β)-chain at a slower rate; it has no activity on the γ-chain. The enzyme exhibits the same specificity with fibrin, cleaving the α-chain more rapidly than the β-chain. Fibrolase was shown to have very effective thrombolytic activity in a reoccluding carotid arterial thrombosis model in the canine. A recombinant version of the enzyme was made in yeast by Amgen, Inc. (Thousand Oaks, CA, USA) and called alfimeprase. Alfimeprase is identical to fibrolase except for a two amino acid truncation at the amino-terminus and the insertion of a new amino-terminal amino acid in the truncated protein; these changes lead to a more stable enzyme for prolonged storage. Alfimeprase was taken into clinical trials by Nuvelo, Inc. (San Carlos, CA), which licensed the enzyme from Amgen. Alfimeprase was successful in Phase I and II clinical trials for peripheral arterial occlusion (PAO) and central venous access device (CVAD) occlusion. However, in Phase III trials alfimeprase did not meet the expected end points in either PAO or CVAD occlusion and in a Phaase II stroke trial, and Nuvelo dropped further development in 2008. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessArticle Imperatoxin A, a Cell-Penetrating Peptide from Scorpion Venom, as a Probe of Ca²⁺-Release Channels/Ryanodine Receptors

by Georgina B. Gurrola, E. Michelle Capes, Fernando Z. Zamudio, Lourival D. Possani and Héctor H. Valdivia

Pharmaceuticals 2010, 3(4), 1093-1107; doi:10.3390/ph3041093

Received: 18 March 2010 / Accepted: 11 April 2010 / Published: 13 April 2010

Abstract

Scorpion venoms are rich in ion channel-modifying peptides, which have proven to be invaluable probes of ion channel structure-function relationship. We previously isolated imperatoxin A (IpTxa), a 3.7 kDa peptide activator of Ca²⁺-release channels/ryanodine receptors (RyRs) [1,2,3] and founding member of

[...] Read more.

Scorpion venoms are rich in ion channel-modifying peptides, which have proven to be invaluable probes of ion channel structure-function relationship. We previously isolated imperatoxin A (IpTxa), a 3.7 kDa peptide activator of Ca²⁺-release channels/ryanodine receptors (RyRs) [1,2,3] and founding member of the calcin family of scorpion peptides. IpTxa folds into a compact, mostly hydrophobic molecule with a cluster of positively-charged, basic residues polarized on one side of the molecule that possibly interacts with the phospholipids of cell membranes. To investigate whether IpTxa permeates external cellular membranes and targets RyRs in vivo, we perfused IpTxa on intact cardiomyocytes while recording field-stimulated intracellular Ca²⁺ transients. To further investigate the cell-penetrating capabilities of the toxin, we prepared thiolated, fluorescent derivatives of IpTxa. Biological activity and spectroscopic properties indicate that these derivatives retain high affinity for RyRs and are only 5- to 10-fold less active than native IpTxa. Our results demonstrate that IpTxa is capable of crossing cell membranes to alter the release of Ca²⁺ in vivo, and has the capacity to carry a large, membrane-impermeable cargo across the plasma membrane, a finding with exciting implications for novel drug delivery. Full article

(This article belongs to the Special Issue Cell-penetrating Peptides 2012)

► Figures

Open AccessReview Animal Toxins: How is Complexity Represented in Databases?

by Florence Jungo, Anne Estreicher, Amos Bairoch, Lydie Bougueleret and Ioannis Xenarios

Toxins 2010, 2(2), 262-282; doi:10.3390/toxins2020261

Received: 22 January 2010 / Revised: 10 February 2010 / Accepted: 11 February 2010 / Published: 21 February 2010

Cited by 7 | Viewed by 6586 | PDF Full-text (648 KB) | HTML Full-text | XML Full-text

Abstract

Peptide toxins synthesized by venomous animals have been extensively studied in the last decades. To be useful to the scientific community, this knowledge has been stored, annotated and made easy to retrieve by several databases. The aim of this article is to present

[...] Read more.

Peptide toxins synthesized by venomous animals have been extensively studied in the last decades. To be useful to the scientific community, this knowledge has been stored, annotated and made easy to retrieve by several databases. The aim of this article is to present what type of information users can access from each database. ArachnoServer and ConoServer focus on spider toxins and cone snail toxins, respectively. UniProtKB, a generalist protein knowledgebase, has an animal toxin-dedicated annotation program that includes toxins from all venomous animals. Finally, the ATDB metadatabase compiles data and annotations from other databases and provides toxin ontology. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessArticle Asp Viper (Vipera aspis) Envenomation: Experience of the Marseille Poison Centre from 1996 to 2008

by Luc De Haro, Mathieu Glaizal, Lucia Tichadou, Ingrid Blanc-Brisset and Maryvonne Hayek-Lanthois

Toxins 2009, 1(2), 100-112; doi:10.3390/toxins1020100

Received: 9 October 2009 / Revised: 18 November 2009 / Accepted: 23 November 2009 / Published: 24 November 2009

Cited by 26 | Viewed by 5876 | PDF Full-text (133 KB) | HTML Full-text | XML Full-text

Abstract

A retrospective case review study of viper envenomations collected by the Marseille’s Poison Centre between 1996 and 2008 was performed. Results: 174 cases were studied (52 grade 1 = G1, 90 G2 and 32 G3). G1 patients received symptomatic treatments (average hospital stay

[...] Read more.

A retrospective case review study of viper envenomations collected by the Marseille’s Poison Centre between 1996 and 2008 was performed. Results: 174 cases were studied (52 grade 1 = G1, 90 G2 and 32 G3). G1 patients received symptomatic treatments (average hospital stay 0.96 day). One hundred and six (106) of the G2/G3 patients were treated with the antivenom Viperfav* (2.1+/-0.9 days in hospital), while 15 of them received symptomatic treatments only (plus one immediate death) (8.1+/-4 days in hospital, 2 of them died). The hospital stay was significantly reduced in the antivenom treated group (p < 0.001), and none of the 106 antivenom treated patients had immediate (anaphylaxis) or delayed (serum sickness) allergic reactions. Conclusion: Viperfav* antivenom was safe and effective for treating asp viper venom-induced toxicity. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessReview The Mauve Stinger Pelagia noctiluca (Forsskål, 1775). Distribution, Ecology, Toxicity and Epidemiology of Stings.

by Gian Luigi Mariottini, Elisabetta Giacco and Luigi Pane

Mar. Drugs 2008, 6(3), 496-513; doi:10.3390/md6030496

Received: 12 March 2008 / Revised: 18 July 2008 / Accepted: 30 July 2008 / Published: 4 September 2008

Viewed by 10166 | PDF Full-text (124 KB) | HTML Full-text | XML Full-text

Abstract

The toxicity of Cnidaria is a subject of concern due to its influence on humans. In particular, jellyfish blooms can highly affect human economical activities, such as bathing, fishery, tourism, etc., as well as the public health. Stinging structures of Cnidaria (nematocysts) produce

[...] Read more.

The toxicity of Cnidaria is a subject of concern due to its influence on humans. In particular, jellyfish blooms can highly affect human economical activities, such as bathing, fishery, tourism, etc., as well as the public health. Stinging structures of Cnidaria (nematocysts) produce remarkable effects on human skin, such as erythema, swelling, burning and vesicles, and at times further severe dermonecrotic, cardio- and neurotoxic effects, which are particularly dangerous in sensitive subjects. In several zones the toxicity of jellyfish is a very important health problem, thus it has stimulated the research on these organisms; to date toxicological research on Cnidarian venoms in the Mediterranean region is not well developed due to the weak poisonousness of venoms of jellyfish and anemones living in this area. In spite of this, during last decades several problems were also caused in the Mediterranean by stinging consequent to Cnidarian blooms mainly caused by Pelagia noctiluca (Forsskål, 1775) which is known to be the most venomous Mediterranean jellyfish. This paper reviews the knowledge on this jellyfish species, particularly considering its occurrence and toxicity. Full article

(This article belongs to the Special Issue Marine Toxins)

Open AccessArticle Purification and Preliminary Crystallographic Analysis of a New Lys49-PLA2 from B. Jararacussu

by Marcelo L. Dos Santos, Fábio H. R. Fagundes, Bruno R. F. Teixeira, Marcos H. Toyama and Ricardo Aparicio

Int. J. Mol. Sci. 2008, 9(5), 736-750; doi:10.3390/ijms9050736

Received: 4 February 2008 / Revised: 6 March 2008 / Accepted: 22 March 2008 / Published: 8 May 2008

Cited by 8 | Viewed by 5617 | PDF Full-text (750 KB) | HTML Full-text | XML Full-text

Abstract

BjVIII is a new myotoxic Lys49-PLA2 isolated from Bothrops jararacussu venom that exhibits atypical effects on human platelet aggregation. To better understand the mode of action of BjVIII, crystallographic studies were initiated. Two crystal forms were obtained, both containing two molecules in the

[...] Read more.

BjVIII is a new myotoxic Lys49-PLA2 isolated from Bothrops jararacussu venom that exhibits atypical effects on human platelet aggregation. To better understand the mode of action of BjVIII, crystallographic studies were initiated. Two crystal forms were obtained, both containing two molecules in the asymmetric unit (ASU). Synchrotron radiation diffraction data were collected to 2.0 °A resolution and 1.9 °A resolution for crystals belonging to the space group P2₁2₁2₁(a = 48:4 A° , b = 65:3 A° , c = 84:3 A° ) and space group P3₁2₁ (a = b = 55:7 A° , c = 127:9 A° ), respectively. Refinement is currently in progress and the refined structures are expected to shed light on the unusual platelet aggregation activity observed for BjVIII. Full article

(This article belongs to the Special Issue Protein Crystallography)

Open AccessArticle Comparison of the Biological Properties of Several Marine Sponge-Derived Sesquiterpenoid Quinones

by Cherie A Motti, Marie-Lise Bourguet-Kondracki, Arlette Longeon, Jason R Doyle, Lyndon E Llewellyn, Dianne M Tapiolas and Ping Yin

Molecules 2007, 12(7), 1376-1388; doi:10.3390/12071376

Received: 18 June 2007 / Revised: 6 July 2007 / Accepted: 9 July 2007 / Published: 11 July 2007

Cited by 16 | Viewed by 5462 | PDF Full-text (102 KB) | HTML Full-text | XML Full-text

Abstract

Eight naturally occurring marine-sponge derived sesquiterpenoid quinones wereevaluated as potential inhibitors of pyruvate phosphate dikinase (PPDK), a C₄ plantregulatory enzyme. Of these, the hydroxyquinones ilimaquinone, ethylsmenoquinone andsmenoquinone inhibited PPDK activity with IC₅₀’s (reported with 95% confidenceintervals) of 285.4 (256.4 –

[...] Read more.

Eight naturally occurring marine-sponge derived sesquiterpenoid quinones wereevaluated as potential inhibitors of pyruvate phosphate dikinase (PPDK), a C₄ plantregulatory enzyme. Of these, the hydroxyquinones ilimaquinone, ethylsmenoquinone andsmenoquinone inhibited PPDK activity with IC₅₀’s (reported with 95% confidenceintervals) of 285.4 (256.4 – 317.7), 316.2 (279.2 – 358.1) and 556.0 (505.9 – 611.0) μM,respectively, as well as being phytotoxic to the C₄ plant Digitaria ciliaris. The potentialanti-inflammatory activity of these compounds, using bee venom phospholipase A₂(PLA₂), was also evaluated. Ethylsmenoquinone, smenospongiarine, smenospongidine andilimaquinone inhibited PLA₂ activity (% inhibition of 73.2 + 4.8 at 269 μM, 61.5 + 6.1 at242 μM, 41.0 + 0.6 at 224 μM and 36.4 + 8.2 at 279 μM, respectively). SAR analysesindicate that a hydroxyquinone functionality and a short, hydroxide/alkoxide side-chain atC-20 is preferred for inhibition of PPDK activity, and that a larger amine side-chain at C-20 is tolerated for PLA₂ inhibitory activity. Full article

► Figures

Figure 1

Open AccessReview New Conotoxin SO-3 Targeting N-type Voltage-Sensitive Calcium Channels

by Lei Wen, Sheng Yang, Wenxia Zhou, Yongxiang Zhang and Peitang Huang

Mar. Drugs 2006, 4(3), 215-227; doi:10.3390/md403215

Received: 10 March 2006 / Accepted: 30 March 2006 / Published: 6 April 2006

Cited by 6 | Viewed by 6165 | PDF Full-text (232 KB) | HTML Full-text | XML Full-text

Abstract

Selective blockers of the N-type voltage-sensitive calcium (CaV) channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from

[...] Read more.

Selective blockers of the N-type voltage-sensitive calcium (CaV) channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from the venom of Conus striatus, and contains the same 4-loop, 6-cysteine framework (C-C-CC-C-C) as O-superfamily conotoxins. The synthetic SO-3 has high analgesic activity similar to ω-conotoxin MVIIA (MVIIA), a selective N-type CaV channel blocker approved in the USA and Europe for the alleviation of persistent pain states. In electrophysiological studies, SO-3 shows more selectivity towards the N-type CaV channels than MVIIA. The dissimilarity between SO-3 and MVIIA in the primary and tertiary structures is further discussed in an attempt to illustrate the difference in selectivity of SO-3 and MVIIA towards N-type CaV channels. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

Open AccessReview ω-Conotoxins GVIA, MVIIA and CVID: SAR and Clinical Potential

by Christina I. Schroeder and Richard J. Lewis

Mar. Drugs 2006, 4(3), 193-214; doi:10.3390/md403193

Received: 16 February 2006 / Accepted: 28 February 2006 / Published: 6 April 2006

Cited by 15 | Viewed by 7142 | PDF Full-text (419 KB) | HTML Full-text | XML Full-text

Abstract

Highly selective N-type voltage-gated calcium (CaV) channel inhibitors from cone snail venom (the ω-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt (Elan) or synthetic ω-conotoxin MVIIA, was the first ω-conotoxin

[...] Read more.

Highly selective N-type voltage-gated calcium (CaV) channel inhibitors from cone snail venom (the ω-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt (Elan) or synthetic ω-conotoxin MVIIA, was the first ω-conotoxin to be approved by Food and Drug Administration for human use. This review compares the action of three ω-conotoxins, GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved N-type therapeutics that are more useful in the treatment of chronic pain. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

MDPI Contact

Advanced Search

Search Results

MDPI Contact

Advanced Search

Search Results

Years

Subjects

Journals

Article Types

Countries