Toxins in Drug Discovery and Pharmacology

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: closed (30 September 2017) | Viewed by 159232

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Special Issue Editor

Toxicology and Pharmacology, Department Pharmaceutical Sciences, Catholic University Leuven, Herestraat 49 box 922, 3000 Leuven, Belgium
Interests: peptide toxin; small molecules; voltage-gated ion channel; electrophysiology; pharmacology; venom; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as an untapped cocktail of biologically-active compounds, being increasingly recognized as new emerging source of peptide-based therapeutics. Venomous animals are considered to be specialized predators that have evolved the most sophisticated peptide chemistry and neuropharmacology for their own biological purposes by producing venoms that contains a structural and functional diversity of neurotoxins. These neurotoxins have shown to be highly selective ligands for a wide range of ion channels and receptors. Therefore, they represent interesting lead compounds for the development of, for example, analgesics, anti-cancer drugs, drugs for neurological disorders such as multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, etc.

This Special Issue of Toxins aims to provide a comprehensive look at toxins and toxin inspired leads and will focus on the mechanism of action, structure-function and evolution of pharmacological interesting venom components, including but not limited to, recent developments relating to the emergence of venoms as an underutilized source of highly evolved bioactive peptides with clinical potential.

Dr. Steve Peigneur
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • sodium channels

  • potassium channels

  • calcium channels

  • chloride ion channels

  • TRP channels

  • ASIC channels

  • opiate receptors

  • acetylcholine receptors

  • NMDA receptor

  • Antibiotics

  • antimicrobial peptides

  • botulinum toxins

  • cone snail venom peptides

  • spider venom peptides

  • amphibian peptides

  • sea anemone toxins

  • scorpion toxins

  • snake toxins

  • centipede toxins

Published Papers (22 papers)

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Editorial

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4 pages, 209 KiB  
Editorial
Toxins in Drug Discovery and Pharmacology
by Steve Peigneur and Jan Tytgat
Toxins 2018, 10(3), 126; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10030126 - 16 Mar 2018
Cited by 41 | Viewed by 5485
Abstract
Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as an untapped cocktail of biologically active compounds, being increasingly recognized as a new emerging source of peptide-based therapeutics. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)

Research

Jump to: Editorial, Review

12 pages, 1902 KiB  
Article
The Peptide PnPP-19, a Spider Toxin Derivative, Activates μ-Opioid Receptors and Modulates Calcium Channels
by Ana C. N. Freitas, Steve Peigneur, Flávio H. P. Macedo, José E. Menezes-Filho, Paul Millns, Liciane F. Medeiros, Maria A. Arruda, Jader Cruz, Nicholas D. Holliday, Jan Tytgat, Gareth Hathway and Maria E. De Lima
Toxins 2018, 10(1), 43; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10010043 - 15 Jan 2018
Cited by 14 | Viewed by 6623
Abstract
The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, [...] Read more.
The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, μ and δ opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for μ-, δ- and/or κ-opioid receptors. Furthermore, we also studied the modulation of calcium influx driven by PnPP-19 in dorsal root ganglion neurons, and analyzed whether this modulation was opioid-mediated. PnPP-19 selectively activates μ-opioid receptors inducing indirectly inhibition of calcium channels and hereby impairing calcium influx in dorsal root ganglion (DRG) neurons. Interestingly, notwithstanding the activation of opioid receptors, PnPP-19 does not induce β-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates μ-opioid receptors. The lack of β-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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25 pages, 2965 KiB  
Article
Azemiopsin, a Selective Peptide Antagonist of Muscle Nicotinic Acetylcholine Receptor: Preclinical Evaluation as a Local Muscle Relaxant
by Irina V. Shelukhina, Maxim N. Zhmak, Alexander V. Lobanov, Igor A. Ivanov, Alexandra I. Garifulina, Irina N. Kravchenko, Ekaterina A. Rasskazova, Margarita A. Salmova, Elena A. Tukhovskaya, Vladimir A. Rykov, Gulsara A. Slashcheva, Natalya S. Egorova, Inessa S. Muzyka, Victor I. Tsetlin and Yuri N. Utkin
Toxins 2018, 10(1), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10010034 - 07 Jan 2018
Cited by 24 | Viewed by 5481
Abstract
Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we [...] Read more.
Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we investigated its preclinical profile in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency. The peptide effectively inhibited (IC50 ~ 19 nM) calcium response of muscle nAChR evoked by 30 μM (EC100) acetylcholine but was less potent (IC50 ~ 3 μM) at α7 nAChR activated by 10 μM (EC50) acetylcholine and had a low affinity to α4β2 and α3-containing nAChR, as well as to GABAA or 5HT3 receptors. Its muscle relaxant effect was demonstrated at intramuscular injection to mice at doses of 30–300 µg/kg, 30 µg/kg being the initial effective dose and 90 µg/kg—the average effective dose. The maximal muscle relaxant effect of Az was achieved in 10 min after the administration and elimination half-life of Az in mice was calculated as 20–40 min. The longest period of Az action observed at a dose of 300 µg/kg was 55 min. The highest acute toxicity (LD50 510 μg/kg) was observed at intravenous injection of Az, at intramuscular or intraperitoneal administration it was less toxic. The peptide showed practically no immunotoxic, allergenic or mutagenic capacity. Overall, the results demonstrate that Az has good drug-like properties for the application as local muscle relaxant and in its parameters, is not inferior to the relaxants currently used. However, some Az modification might be effective to extend its narrow therapeutic window, a typical characteristic and a weak point of all nondepolarizing myorelaxants. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Bee Venom Suppresses the Differentiation of Preadipocytes and High Fat Diet-Induced Obesity by Inhibiting Adipogenesis
by Se-Yun Cheon, Kyung-Sook Chung, Seong-Soo Roh, Yun-Yeop Cha and Hyo-Jin An
Toxins 2018, 10(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10010009 - 24 Dec 2017
Cited by 12 | Viewed by 7077
Abstract
Bee venom (BV) has been widely used in the treatment of certain immune-related diseases. It has been used for pain relief and in the treatment of chronic inflammatory diseases. Despite its extensive use, there is little documented evidence to demonstrate its medicinal utility [...] Read more.
Bee venom (BV) has been widely used in the treatment of certain immune-related diseases. It has been used for pain relief and in the treatment of chronic inflammatory diseases. Despite its extensive use, there is little documented evidence to demonstrate its medicinal utility against obesity. In this study, we demonstrated the inhibitory effects of BV on adipocyte differentiation in 3T3-L1 cells and on a high fat diet (HFD)-induced obesity mouse model through the inhibition of adipogenesis. BV inhibited lipid accumulation, visualized by Oil Red O staining, without cytotoxicity in the 3T3-L1 cells. Male C57BL/6 mice were fed either a HFD or a control diet for 8 weeks, and BV (0.1 mg/kg or 1 mg/kg) or saline was injected during the last 4 weeks. BV-treated mice showed a reduced body weight gain. BV was shown to inhibit adipogenesis by downregulating the expression of the transcription factors CCAAT/enhancer-binding proteins (C/EBPs) and the peroxisome proliferator-activated receptor gamma (PPARγ), using RT-qPCR and Western blotting. BV induced the phosphorylation of AMP-activated kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the cell line and in obese mice. These findings demonstrate that BV mediates anti-obesity/differentiation effects by suppressing obesity-related transcription factors. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Molecular Dynamics Simulation Reveals Specific Interaction Sites between Scorpion Toxins and Kv1.2 Channel: Implications for Design of Highly Selective Drugs
by Shouli Yuan, Bin Gao and Shunyi Zhu
Toxins 2017, 9(11), 354; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110354 - 01 Nov 2017
Cited by 6 | Viewed by 4724
Abstract
The Kv1.2 channel plays an important role in the maintenance of resting membrane potential and the regulation of the cellular excitability of neurons, whose silencing or mutations can elicit neuropathic pain or neurological diseases (e.g., epilepsy and ataxia). Scorpion venom contains [...] Read more.
The Kv1.2 channel plays an important role in the maintenance of resting membrane potential and the regulation of the cellular excitability of neurons, whose silencing or mutations can elicit neuropathic pain or neurological diseases (e.g., epilepsy and ataxia). Scorpion venom contains a variety of peptide toxins targeting the pore region of this channel. Despite a large amount of structural and functional data currently available, their detailed interaction modes are poorly understood. In this work, we choose four Kv1.2-targeted scorpion toxins (Margatoxin, Agitoxin-2, OsK-1, and Mesomartoxin) to construct their complexes with Kv1.2 based on the experimental structure of ChTx-Kv1.2. Molecular dynamics simulation of these complexes lead to the identification of hydrophobic patches, hydrogen-bonds, and salt bridges as three essential forces mediating the interactions between this channel and the toxins, in which four Kv1.2-specific interacting amino acids (D353, Q358, V381, and T383) are identified for the first time. This discovery might help design highly selective Kv1.2-channel inhibitors by altering amino acids of these toxins binding to the four channel residues. Finally, our results provide new evidence in favor of an induced fit model between scorpion toxins and K+ channel interactions. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor
by Jiho Choi, Changhoon Jeon, Ji Hwan Lee, Jo Ung Jang, Fu Shi Quan, Kyungjin Lee, Woojin Kim and Sun Kwang Kim
Toxins 2017, 9(11), 351; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110351 - 31 Oct 2017
Cited by 32 | Viewed by 6163
Abstract
Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on [...] Read more.
Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α2-adrenergic receptor antagonist (idazoxan, 50 µg), but not α1-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α2-adrenergic receptor. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Overlooked Short Toxin-Like Proteins: A Shortcut to Drug Design
by Michal Linial, Nadav Rappoport and Dan Ofer
Toxins 2017, 9(11), 350; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110350 - 29 Oct 2017
Cited by 7 | Viewed by 5251
Abstract
Short stable peptides have huge potential for novel therapies and biosimilars. Cysteine-rich short proteins are characterized by multiple disulfide bridges in a compact structure. Many of these metazoan proteins are processed, folded, and secreted as soluble stable folds. These properties are shared by [...] Read more.
Short stable peptides have huge potential for novel therapies and biosimilars. Cysteine-rich short proteins are characterized by multiple disulfide bridges in a compact structure. Many of these metazoan proteins are processed, folded, and secreted as soluble stable folds. These properties are shared by both marine and terrestrial animal toxins. These stable short proteins are promising sources for new drug development. We developed ClanTox (classifier of animal toxins) to identify toxin-like proteins (TOLIPs) using machine learning models trained on a large-scale proteomic database. Insects proteomes provide a rich source for protein innovations. Therefore, we seek overlooked toxin-like proteins from insects (coined iTOLIPs). Out of 4180 short (<75 amino acids) secreted proteins, 379 were predicted as iTOLIPs with high confidence, with as many as 30% of the genes marked as uncharacterized. Based on bioinformatics, structure modeling, and data-mining methods, we found that the most significant group of predicted iTOLIPs carry antimicrobial activity. Among the top predicted sequences were 120 termicin genes from termites with antifungal properties. Structural variations of insect antimicrobial peptides illustrate the similarity to a short version of the defensin fold with antifungal specificity. We also identified 9 proteins that strongly resemble ion channel inhibitors from scorpion and conus toxins. Furthermore, we assigned functional fold to numerous uncharacterized iTOLIPs. We conclude that a systematic approach for finding iTOLIPs provides a rich source of peptides for drug design and innovative therapeutic discoveries. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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1981 KiB  
Article
The Effects of Melittin and Apamin on Airborne Fungi-Induced Chemical Mediator and Extracellular Matrix Production from Nasal Polyp Fibroblasts
by Seung-Heon Shin, Mi-Kyung Ye, Sung-Yong Choi and Kwan-Kyu Park
Toxins 2017, 9(11), 348; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110348 - 27 Oct 2017
Cited by 17 | Viewed by 4732
Abstract
Melittin and apamin are the main components of bee venom and they have been known to have anti-inflammatory and anti-fibrotic properties. The aim of this study was to evaluate the effect of melittin and apamin on airborne fungi-induced chemical mediator and extracellular matrix [...] Read more.
Melittin and apamin are the main components of bee venom and they have been known to have anti-inflammatory and anti-fibrotic properties. The aim of this study was to evaluate the effect of melittin and apamin on airborne fungi-induced chemical mediator and extracellular matrix (ECM) production in nasal fibroblasts. Primary nasal fibroblasts were isolated from nasal polyps, which were collected during endoscopic sinus surgery. Nasal fibroblasts were treated with Alternaria and Aspergillus. The effects of melittin and apamin on the production of interleukin (IL)-6 and IL-8 were determined with enzyme linked immunosorbent assay. ECM mRNA and protein expressions were determined with the use of quantitative RT-PCR and Western blot. Alternaria-induced IL-6 and IL-8 production was significantly inhibited by apamin. However, melittin did not influence the production of IL-6 and IL-8 from nasal fibroblasts. Melittin or apamin significantly inhibited collagen type I, TIMP-1, and MMP-9 mRNA expression and protein production from nasal fibroblasts. Melittin and apamin inhibited Alternaria-induced phosphorylation of Smad 2/3 and p38 MAPK. Melittin and apamin can inhibit the fungi-induced production of chemical mediators and ECM from nasal fibroblasts. These results suggest the possible role of melittin and apamin in the treatment of fungi induced airway inflammatory diseases. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Anticoagulant Activity of Low-Molecular Weight Compounds from Heterometrus laoticus Scorpion Venom
by Thien Vu Tran, Anh Ngoc Hoang, Trang Thuy Thi Nguyen, Trung Van Phung, Khoa Cuu Nguyen, Alexey V. Osipov, Igor A. Ivanov, Victor I. Tsetlin and Yuri N. Utkin
Toxins 2017, 9(11), 343; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110343 - 26 Oct 2017
Cited by 14 | Viewed by 5058
Abstract
Scorpion venoms are complex polypeptide mixtures, the ion channel blockers and antimicrobial peptides being the best studied components. The coagulopathic properties of scorpion venoms are poorly studied and the data about substances exhibiting these properties are very limited. During research on the Heterometrus [...] Read more.
Scorpion venoms are complex polypeptide mixtures, the ion channel blockers and antimicrobial peptides being the best studied components. The coagulopathic properties of scorpion venoms are poorly studied and the data about substances exhibiting these properties are very limited. During research on the Heterometrus laoticus scorpion venom, we have isolated low-molecular compounds with anticoagulant activity. Determination of their structure has shown that one of them is adenosine, and two others are dipeptides LeuTrp and IleTrp. The anticoagulant properties of adenosine, an inhibitor of platelet aggregation, are well known, but its presence in scorpion venom is shown for the first time. The dipeptides did not influence the coagulation time in standard plasma coagulation tests. However, similarly to adenosine, both peptides strongly prolonged the bleeding time from mouse tail and in vitro clot formation in whole blood. The dipeptides inhibited the secondary phase in platelet aggregation induced by ADP, and IleTrp decreased an initial rate of platelet aggregation induced by collagen. This suggests that their anticoagulant effects may be realized through the deterioration of platelet function. The ability of short peptides from venom to slow down blood coagulation and their presence in scorpion venom are established for the first time. Further studies are needed to elucidate the precise molecular mechanism of dipeptide anticoagulant activity. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Can Inhibitors of Snake Venom Phospholipases A2 Lead to New Insights into Anti-Inflammatory Therapy in Humans? A Theoretical Study
by Thaís A. Sales, Silvana Marcussi, Elaine F. F. Da Cunha, Kamil Kuca and Teodorico C. Ramalho
Toxins 2017, 9(11), 341; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9110341 - 25 Oct 2017
Cited by 19 | Viewed by 5466
Abstract
Human phospholipase A2 (hPLA2) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with [...] Read more.
Human phospholipase A2 (hPLA2) of the IIA group (HGIIA) catalyzes the hydrolysis of membrane phospholipids, producing arachidonic acid and originating potent inflammatory mediators. Therefore, molecules that can inhibit this enzyme are a source of potential anti-inflammatory drugs, with different action mechanisms of known anti-inflammatory agents. For the study and development of new anti-inflammatory drugs with this action mechanism, snake venom PLA2 (svPLA2) can be employed, since the svPLA2 has high similarity with the human PLA2 HGIIA. Despite the high similarity between these secretory PLA2s, it is still not clear if these toxins can really be employed as an experimental model to predict the interactions that occur with the human PLA2 HGIIA and its inhibitors. Thus, the present study aims to compare and evaluate, by means of theoretical calculations, docking and molecular dynamics simulations, as well as experimental studies, the interactions of human PLA2 HGIIA and two svPLA2s, Bothrops toxin II and Crotoxin B (BthTX-II and CB, respectively). Our theoretical findings corroborate experimental data and point out that the human PLA2 HGIIA and svPLA2 BthTX-II lead to similar interactions with the studied compounds. From our results, the svPLA2 BthTX-II can be used as an experimental model for the development of anti-inflammatory drugs for therapy in humans. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Anti-Salmonella Activity Modulation of Mastoparan V1—A Wasp Venom Toxin—Using Protease Inhibitors, and Its Efficient Production via an Escherichia coli Secretion System
by Yeon Jo Ha, Sam Woong Kim, Chae Won Lee, Chang-Hwan Bae, Joo-Hong Yeo, Il-Suk Kim, Sang Wan Gal, Jin Hur, Ho-Kyoung Jung, Min-Ju Kim and Woo Young Bang
Toxins 2017, 9(10), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9100321 - 13 Oct 2017
Cited by 8 | Viewed by 5059
Abstract
A previous study highlighted that mastoparan V1 (MP-V1), a mastoparan from the venom of the social wasp Vespula vulgaris, is a potent antimicrobial peptide against Salmonella infection, which causes enteric diseases. However, there exist some limits for its practical application due to [...] Read more.
A previous study highlighted that mastoparan V1 (MP-V1), a mastoparan from the venom of the social wasp Vespula vulgaris, is a potent antimicrobial peptide against Salmonella infection, which causes enteric diseases. However, there exist some limits for its practical application due to the loss of its activity in an increased bacterial density and the difficulty of its efficient production. In this study, we first modulated successfully the antimicrobial activity of synthetic MP-V1 against an increased Salmonella population using protease inhibitors, and developed an Escherichia coli secretion system efficiently producing active MP-V1. The protease inhibitors used, except pepstatin A, significantly increased the antimicrobial activity of the synthetic MP-V1 at minimum inhibitory concentrations (determined against 106 cfu/mL of population) against an increased population (108 cfu/mL) of three different Salmonella serotypes, Gallinarum, Typhimurium and Enteritidis. Meanwhile, the E. coli strain harboring OmpA SS::MP-V1 was identified to successfully secrete active MP-V1 into cell-free supernatant, whose antimicrobial activity disappeared in the increased population (108 cfu/mL) of Salmonella Typhimurium recovered by adding a protease inhibitor cocktail. Therefore, it has been concluded that our challenge using the E. coli secretion system with the protease inhibitors is an attractive strategy for practical application of peptide toxins, such as MP-V1. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
The Influence of Resiniferatoxin (RTX) and Tetrodotoxin (TTX) on the Distribution, Relative Frequency, and Chemical Coding of Noradrenergic and Cholinergic Nerve Fibers Supplying the Porcine Urinary Bladder Wall
by Ewa Lepiarczyk, Agnieszka Bossowska, Jerzy Kaleczyc, Agnieszka Skowrońska, Marta Majewska, Michal Majewski and Mariusz Majewski
Toxins 2017, 9(10), 310; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9100310 - 03 Oct 2017
Cited by 10 | Viewed by 5263
Abstract
The present study investigated the influence of intravesically instilled resiniferatoxin (RTX) or tetrodotoxin (TTX) on the distribution, number, and chemical coding of noradrenergic and cholinergic nerve fibers (NF) supplying the urinary bladder in female pigs. Samples from the bladder wall were processed for [...] Read more.
The present study investigated the influence of intravesically instilled resiniferatoxin (RTX) or tetrodotoxin (TTX) on the distribution, number, and chemical coding of noradrenergic and cholinergic nerve fibers (NF) supplying the urinary bladder in female pigs. Samples from the bladder wall were processed for double-labelling immunofluorescence with antibodies against cholinergic and noradrenergic markers and some other neurotransmitter substances. Both RTX and TTX caused a significant decrease in the number of cholinergic NF in the urinary bladder wall (in the muscle coat, submucosa, and beneath the urothelium). RTX instillation resulted in a decrease in the number of noradrenergic NF in the submucosa and urothelium, while TTX treatment caused a significant increase in the number of these axons in all the layers. The most remarkable changes in the chemical coding of the NF comprised a distinct decrease in the number of the cholinergic NF immunoreactive to CGRP (calcitonin gene-related peptide), nNOS (neuronal nitric oxide synthase), SOM (somatostatin) or VIP (vasoactive intestinal polypeptide), and an increase in the number of noradrenergic NF immunopositive to GAL (galanin) or nNOS, both after RTX or TTX instillation. The present study is the first to suggest that both RTX and TTX can modify the number of noradrenergic and cholinergic NF supplying the porcine urinary bladder. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Antiallodynic Effects of Bee Venom in an Animal Model of Complex Regional Pain Syndrome Type 1 (CRPS-I)
by Sung Hyun Lee, Jae Min Lee, Yun Hong Kim, Jung Hyun Choi, Seung Hwan Jeon, Dong Kyu Kim, Hyeon Do Jeong, You Jung Lee and Hue Jung Park
Toxins 2017, 9(9), 285; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9090285 - 15 Sep 2017
Cited by 9 | Viewed by 7729
Abstract
Neuropathic pain in a chronic post-ischaemic pain (CPIP) model mimics the symptoms of complex regional pain syndrome type I (CRPS I). The administration of bee venom (BV) has been utilized in Eastern medicine to treat chronic inflammatory diseases accompanying pain. However, the analgesic [...] Read more.
Neuropathic pain in a chronic post-ischaemic pain (CPIP) model mimics the symptoms of complex regional pain syndrome type I (CRPS I). The administration of bee venom (BV) has been utilized in Eastern medicine to treat chronic inflammatory diseases accompanying pain. However, the analgesic effect of BV in a CPIP model remains unknown. The application of a tight-fitting O-ring around the left ankle for a period of 3 h generated CPIP in C57/Bl6 male adult mice. BV (1 mg/kg ; 1, 2, and 3 times) was administered into the SC layer of the hind paw, and the antiallodynic effects were investigated using the von Frey test and by measuring the expression of neurokinin type 1 (NK-1) receptors in dorsal root ganglia (DRG). The administration of BV dose-dependently reduced the pain withdrawal threshold to mechanical stimuli compared with the pre-administration value and with that of the control group. After the development of the CPIP model, the expression of NK-1 receptors in DRG increased and then decreased following the administration of BV. SC administration of BV results in the attenuation of allodynia in a mouse model of CPIP. The antiallodynic effect was objectively proven through a reduction in the increased expression of NK-1 receptors in DRG. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
Cobra Venom Factor and Ketoprofen Abolish the Antitumor Effect of Nerve Growth Factor from Cobra Venom
by Alexey V. Osipov, Tatiana I. Terpinskaya, Tatiana E. Kuznetsova, Elena L. Ryzhkovskaya, Vladimir S. Lukashevich, Julia A. Rudnichenko, Vladimir S. Ulashchyk, Vladislav G. Starkov and Yuri N. Utkin
Toxins 2017, 9(9), 274; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9090274 - 06 Sep 2017
Cited by 4 | Viewed by 4580
Abstract
We showed recently that nerve growth factor (NGF) from cobra venom inhibited the growth of Ehrlich ascites carcinoma (EAC) inoculated subcutaneously in mice. Here, we studied the influence of anti-complementary cobra venom factor (CVF) and the non-steroidal anti-inflammatory drug ketoprofen on the antitumor [...] Read more.
We showed recently that nerve growth factor (NGF) from cobra venom inhibited the growth of Ehrlich ascites carcinoma (EAC) inoculated subcutaneously in mice. Here, we studied the influence of anti-complementary cobra venom factor (CVF) and the non-steroidal anti-inflammatory drug ketoprofen on the antitumor NGF effect, as well as on NGF-induced changes in EAC histological patterns, the activity of lactate and succinate dehydrogenases in tumor cells and the serum level of some cytokines. NGF, CVF and ketoprofen reduced the tumor volume by approximately 72%, 68% and 30%, respectively. The antitumor effect of NGF was accompanied by an increase in the lymphocytic infiltration of the tumor tissue, the level of interleukin 1β and tumor necrosis factor α in the serum, as well as the activity of lactate and succinate dehydrogenases in tumor cells. Simultaneous administration of NGF with either CVF or ketoprofen abolished the antitumor effect and reduced all other effects of NGF, whereas NGF itself significantly decreased the antitumor action of both CVF and ketoprofen. Thus, the antitumor effect of NGF critically depended on the status of the immune system and was abolished by the disturbance of the complement system; the disturbance of the inflammatory response canceled the antitumor effect as well. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Article
High Throughput Identification of Antimicrobial Peptides from Fish Gastrointestinal Microbiota
by Bo Dong, Yunhai Yi, Lifeng Liang and Qiong Shi
Toxins 2017, 9(9), 266; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9090266 - 30 Aug 2017
Cited by 28 | Viewed by 6013
Abstract
Antimicrobial peptides (AMPs) are a group of small peptides, which are secreted by almost all creatures in nature. They have been explored in therapeutic and agricultural aspects as they are toxic to many bacteria. A considerable amount of work has been conducted in [...] Read more.
Antimicrobial peptides (AMPs) are a group of small peptides, which are secreted by almost all creatures in nature. They have been explored in therapeutic and agricultural aspects as they are toxic to many bacteria. A considerable amount of work has been conducted in analyzing 16S and metagenomics of the gastrointestinal (GI) microbiome of grass carp (Ctenopharyngodon idellus). However, these datasets are still untapped resources. In this present study, a homologous search was performed to predict AMPs from our newly generated metagenome of grass carp. We identified five AMPs with high similarities to previously reported bacterial toxins, such as lantibiotic and class II bacteriocins. In addition, we observed that the top abundant genus in the GI microbiota of the grass carp was generally consistent with the putative AMP-producing strains, which are mainly from Lactobacillales. Furthermore, we constructed the phylogenetic relationship of these putative AMP-producing bacteria existing in the GI of grass carp and some popular commercial probiotics (commonly used for microecologics), demonstrating that they are closely related. Thus, these strains have the potential to be developed into novel microecologics. In a word, we provide a high-throughput way to discover AMPs from fish GI microbiota, which can be developed as alternative pathogen antagonists (toxins) for microecologics or probiotic supplements. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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6638 KiB  
Article
Lengths of the C-Terminus and Interconnecting Loops Impact Stability of Spider-Derived Gating Modifier Toxins
by Akello J. Agwa, Yen-Hua Huang, David J. Craik, Sónia T. Henriques and Christina I. Schroeder
Toxins 2017, 9(8), 248; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9080248 - 12 Aug 2017
Cited by 21 | Viewed by 4888
Abstract
Spider gating modifier toxins (GMTs) are potent modulators of voltage-gated ion channels and have thus attracted attention as drug leads for several pathophysiological conditions. GMTs contain three disulfide bonds organized in an inhibitory cystine knot, which putatively confers them with high stability; however, [...] Read more.
Spider gating modifier toxins (GMTs) are potent modulators of voltage-gated ion channels and have thus attracted attention as drug leads for several pathophysiological conditions. GMTs contain three disulfide bonds organized in an inhibitory cystine knot, which putatively confers them with high stability; however, thus far, there has not been a focused study to establish the stability of GMTs in physiological conditions. We examined the resistance of five GMTs including GpTx-1, HnTx-IV, HwTx-IV, PaurTx-3 and SgTx-1, to pH, thermal and proteolytic degradation. The peptides were stable under physiological conditions, except SgTx-1, which was susceptible to proteolysis, probably due to a longer C-terminus compared to the other peptides. In non-physiological conditions, the five peptides withstood chaotropic degradation, and all but SgTx-1 remained intact after prolonged exposure to high temperature; however, the peptides were degraded in strongly alkaline solutions. GpTx-1 and PaurTx-3 were more resistant to basic hydrolysis than HnTx-IV, HwTx-IV and SgTx-1, probably because a shorter interconnecting loop 3 on GpTx-1 and PaurTx-3 may stabilize interactions between the C-terminus and the hydrophobic patch. Here, we establish that most GMTs are exceptionally stable, and propose that, in the design of GMT-based therapeutics, stability can be enhanced by optimizing the C-terminus in terms of length, and increased interactions with the hydrophobic patch. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Review

Jump to: Editorial, Research

5169 KiB  
Review
Cone Snails: A Big Store of Conotoxins for Novel Drug Discovery
by Bingmiao Gao, Chao Peng, Jiaan Yang, Yunhai Yi, Junqing Zhang and Qiong Shi
Toxins 2017, 9(12), 397; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9120397 - 07 Dec 2017
Cited by 93 | Viewed by 22315
Abstract
Marine drugs have developed rapidly in recent decades. Cone snails, a group of more than 700 species, have always been one of the focuses for new drug discovery. These venomous snails capture prey using a diverse array of unique bioactive neurotoxins, usually named [...] Read more.
Marine drugs have developed rapidly in recent decades. Cone snails, a group of more than 700 species, have always been one of the focuses for new drug discovery. These venomous snails capture prey using a diverse array of unique bioactive neurotoxins, usually named as conotoxins or conopeptides. These conotoxins have proven to be valuable pharmacological probes and potential drugs due to their high specificity and affinity to ion channels, receptors, and transporters in the nervous systems of target prey and humans. Several research groups, including ours, have examined the venom gland of cone snails using a combination of transcriptomic and proteomic sequencing, and revealed the existence of hundreds of conotoxin transcripts and thousands of conopeptides in each Conus species. Over 2000 nucleotide and 8000 peptide sequences of conotoxins have been published, and the number is still increasing quickly. However, more than 98% of these sequences still lack 3D structural and functional information. With the rapid development of genomics and bioinformatics in recent years, functional predictions and investigations on conotoxins are making great progress in promoting the discovery of novel drugs. For example, ω-MVIIA was approved by the U.S. Food and Drug Administration in 2004 to treat chronic pain, and nine more conotoxins are at various stages of preclinical or clinical evaluation. In short, the genus Conus, the big family of cone snails, has become an important genetic resource for conotoxin identification and drug development. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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6059 KiB  
Review
Direct Fibrinolytic Snake Venom Metalloproteinases Affecting Hemostasis: Structural, Biochemical Features and Therapeutic Potential
by Eladio F. Sanchez, Renzo J. Flores-Ortiz, Valeria G. Alvarenga and Johannes A. Eble
Toxins 2017, 9(12), 392; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9120392 - 05 Dec 2017
Cited by 43 | Viewed by 8235
Abstract
Snake venom metalloproteinases (SVMPs) are predominant in viperid venoms, which provoke hemorrhage and affect hemostasis and thrombosis. P-I class enzymes consist only of a single metalloproteinase domain. Despite sharing high sequence homology, only some of them induce hemorrhage. They have direct fibrin(ogen)olytic activity. [...] Read more.
Snake venom metalloproteinases (SVMPs) are predominant in viperid venoms, which provoke hemorrhage and affect hemostasis and thrombosis. P-I class enzymes consist only of a single metalloproteinase domain. Despite sharing high sequence homology, only some of them induce hemorrhage. They have direct fibrin(ogen)olytic activity. Their main biological substrate is fibrin(ogen), whose Aα-chain is degraded rapidly and independently of activation of plasminogen. It is important to understand their biochemical and physiological mechanisms, as well as their applications, to study the etiology of some human diseases and to identify sites of potential intervention. As compared to all current antiplatelet therapies to treat cardiovascular events, the SVMPs have outstanding biochemical attributes: (a) they are insensitive to plasma serine proteinase inhibitors; (b) they have the potential to avoid bleeding risk; (c) mechanistically, they are inactivated/cleared by α2-macroglobulin that limits their range of action in circulation; and (d) few of them also impair platelet aggregation that represent an important target for therapeutic intervention. This review will briefly highlight the structure–function relationships of these few direct-acting fibrinolytic agents, including, barnettlysin-I, isolated from Bothrops barnetti venom, that could be considered as potential agent to treat major thrombotic disorders. Some of their pharmacological advantages are compared with plasmin. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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685 KiB  
Review
Targeting Metastasis with Snake Toxins: Molecular Mechanisms
by Félix A. Urra and Ramiro Araya-Maturana
Toxins 2017, 9(12), 390; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9120390 - 30 Nov 2017
Cited by 23 | Viewed by 6241
Abstract
Metastasis involves the migration of cancer cells from a primary tumor to invade and establish secondary tumors in distant organs, and it is the main cause for cancer-related deaths. Currently, the conventional cytostatic drugs target the proliferation of malignant cells, being ineffective in [...] Read more.
Metastasis involves the migration of cancer cells from a primary tumor to invade and establish secondary tumors in distant organs, and it is the main cause for cancer-related deaths. Currently, the conventional cytostatic drugs target the proliferation of malignant cells, being ineffective in metastatic disease. This highlights the need to find new anti-metastatic drugs. Toxins isolated from snake venoms are a natural source of potentially useful molecular scaffolds to obtain agents with anti-migratory and anti-invasive effects in cancer cells. While there is greater evidence concerning the mechanisms of cell death induction of several snake toxin classes on cancer cells; only a reduced number of toxin classes have been reported on (i.e., disintegrins/disintegrin-like proteins, C-type lectin-like proteins, C-type lectins, serinproteases, cardiotoxins, snake venom cystatins) as inhibitors of adhesion, migration, and invasion of cancer cells. Here, we discuss the anti-metastatic mechanisms of snake toxins, distinguishing three targets, which involve (1) inhibition of extracellular matrix components-dependent adhesion and migration, (2) inhibition of epithelial-mesenchymal transition, and (3) inhibition of migration by alterations in the actin/cytoskeleton network. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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547 KiB  
Review
Therapeutic Potential of Cholera Toxin B Subunit for the Treatment of Inflammatory Diseases of the Mucosa
by Joshua M. Royal and Nobuyuki Matoba
Toxins 2017, 9(12), 379; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9120379 - 23 Nov 2017
Cited by 22 | Viewed by 8168
Abstract
Cholera toxin B subunit (CTB) is a mucosal immunomodulatory protein that induces robust mucosal and systemic antibody responses. This well-known biological activity has been exploited in cholera prevention (as a component of Dukoral® vaccine) and vaccine development for decades. On the other [...] Read more.
Cholera toxin B subunit (CTB) is a mucosal immunomodulatory protein that induces robust mucosal and systemic antibody responses. This well-known biological activity has been exploited in cholera prevention (as a component of Dukoral® vaccine) and vaccine development for decades. On the other hand, several studies have investigated CTB’s immunotherapeutic potential in the treatment of inflammatory diseases such as Crohn’s disease and asthma. Furthermore, we recently found that a variant of CTB could induce colon epithelial wound healing in mouse colitis models. This review summarizes the possible mechanisms behind CTB’s anti-inflammatory activity and discuss how the protein could impact mucosal inflammatory disease treatment. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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Review
Animal Toxins Providing Insights into TRPV1 Activation Mechanism
by Matan Geron, Adina Hazan and Avi Priel
Toxins 2017, 9(10), 326; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9100326 - 16 Oct 2017
Cited by 34 | Viewed by 7224
Abstract
Beyond providing evolutionary advantages, venoms offer unique research tools, as they were developed to target functionally important proteins and pathways. As a key pain receptor in the nociceptive pathway, transient receptor potential vanilloid 1 (TRPV1) of the TRP superfamily has been shown to [...] Read more.
Beyond providing evolutionary advantages, venoms offer unique research tools, as they were developed to target functionally important proteins and pathways. As a key pain receptor in the nociceptive pathway, transient receptor potential vanilloid 1 (TRPV1) of the TRP superfamily has been shown to be a target for several toxins, as a way of producing pain to deter predators. Importantly, TRPV1 is involved in thermoregulation, inflammation, and acute nociception. As such, toxins provide tools to understand TRPV1 activation and modulation, a critical step in advancing pain research and the development of novel analgesics. Indeed, the phytotoxin capsaicin, which is the spicy chemical in chili peppers, was invaluable in the original cloning and characterization of TRPV1. The unique properties of each subsequently characterized toxin have continued to advance our understanding of functional, structural, and biophysical characteristics of TRPV1. By building on previous reviews, this work aims to provide a comprehensive summary of the advancements made in TRPV1 research in recent years by employing animal toxins, in particular DkTx, RhTx, BmP01, Echis coloratus toxins, APHCs and HCRG21. We examine each toxin’s functional aspects, behavioral effects, and structural features, all of which have contributed to our current knowledge of TRPV1. We additionally discuss the key features of TRPV1’s outer pore domain, which proves to be the target of the currently discussed toxins. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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638 KiB  
Review
Botulinum Toxin for the Treatment of Neuropathic Pain
by JungHyun Park and Hue Jung Park
Toxins 2017, 9(9), 260; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins9090260 - 24 Aug 2017
Cited by 133 | Viewed by 15933
Abstract
Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves [...] Read more.
Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves inhibiting the release of inflammatory mediators and peripheral neurotransmitters from sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, and peripheral neuralgia. The purpose of this review is to summarize the experimental and clinical evidence of the mechanism by which BoNT acts on various types of neuropathic pain and describe why BoNT can be applied as treatment. The PubMed database was searched from 1988 to May 2017. Recent studies have demonstrated that BoNT injections are effective treatments for post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain, such as poststroke pain and spinal cord injury. Full article
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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