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

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 75733

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Prof. Dr. Philip Lazarovici

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Guest Editor

Laboratory of Neuropharmacology, Neuro-oncology and Neural Engineering, School of Pharmacy-Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
Interests: animal venoms; neurotoxins; nerve growth factors; disintegrins; neurotoxicity and neuroprotection; neurodegenerative diseases; neuropharmacology and neurooncology; preclinical pharmacological assessments; in vitro and in vivo model systems; drug development

Special Issue Information

Dear Colleagues,

Toxins represent a wide range of biologically active chemical structures including protein and peptide toxins that target with high selectivity and efficacy a variety of membrane receptors, ion channels, enzymes and intracellular signaling molecules. Toxins can therefore be seen as large natural libraries of potential new drugs that are continuously selected and highly refined by the evolution process, up to the point where every molecule is endowed with the optimal pharmacological properties. Toxins therefore, are unique pharmacological tools to investigate cellular and systems physiology and are highly valuable in the context of drug discovery and development as well as in therapy of different diseases. Nevertheless the use of venoms and derived toxins for drug discovery is a rapidly emerging but still mostly unrealized prospective, due to several major difficulties such as availability, the chemical complexity of venoms and the tedious and expensive process of drug development. The biopharmaceutical industry is in dire need of innovation since intense progress in the identification of “druggable” targets at the molecular level has not necessarily resulted in the identification of novel drugs. Successes in bringing to market therapeutic monoclonal antibodies, recombinant proteins and synthetic peptides have increased the attractiveness of “biologics” as novel drugs, with several hundred antibodies and peptides in the clinic and many others under clinical evaluation. Therefore, proteins and peptide toxins from animal venoms are representing a novel class of biologics. They are very potent, highly target-specific but have much lower immunogenicity than antibodies and show much higher resistance to degradation than linear peptides. Drugs from toxins are few, but those developed contributed significantly to therapy of pain, cancer, blood pressure and hemostasis control. These aspects will be emphasized in this Special Issue by selected toxins. Through the combination of venomics, transcriptomics, proteomics, recombinant proteins molecular pharming, combinatorial peptide synthesis and development of targeted micro and nano carrier delivery systems, the contribution of toxins to the future drug development seems to be very promising.

Prof. Philip Lazarovici
Guest Editor

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Keywords

Venom
Toxin
Peptide
Lead compound
Therapeutic applications
Disintegrin
C- type lectin related proteins
Antiplatelets and analgesic drugs
Pain
Nanotechnology
Medicine

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Published Papers (12 papers)

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Research

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10 pages, 1493 KiB

Open AccessArticle

Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain

by Seunghui Woo, Geehoon Chung, Hyunsu Bae and Sun Kwang Kim

Toxins 2019, 11(8), 477; https://doi.org/10.3390/toxins11080477 - 19 Aug 2019

Cited by 5 | Viewed by 4246

Abstract

Bee venom (BV) has a long history of being used in traditional Korean medicine to relieve pain. Here, we investigated the effect of BV-derived phospholipase A2 (bvPLA2), a major component of BV, on peripheral nerve injury-induced neuropathic pain in rats. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to induce neuropathic pain, and paw withdrawal thresholds were measured using von Frey test. Mechanical allodynia, the representative symptom of neuropathic pain, was manifested following SNL and persisted for several weeks. The repetitive bvPLA2 treatment (0.2 mg/kg/day, i.p.) for two days significantly relieved the SNL-induced mechanical allodynia. The antiallodynic effect of bvPLA2 was blocked by spinal pretreatment with α1-adrenergic antagonist prazosin (30 μg, i.t.) but not with α2-adrenergic antagonist idazoxan (50 μg, i.t.). Also, the spinal application of α1-adrenergic agonist phenylephrine (50 μg, i.t.) reduced mechanical allodynia. These results indicate that bvPLA2 could relieve nerve injury-induced neuropathic mechanical allodynia through the activation of spinal α1-adrenergic receptors. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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9 pages, 1746 KiB

Open AccessArticle

Comparison of the Protective Effects of Bee Venom Extracts with Varying PLA₂ Compositions in a Mouse Model of Parkinson’s Disease

by Kyung Hwa Kim, Minhwan Kim, Jaehwan Lee, Hat Nim Jeon, Se Hyun Kim and Hyunsu Bae

Toxins 2019, 11(6), 358; https://doi.org/10.3390/toxins11060358 - 19 Jun 2019

Cited by 21 | Viewed by 4384

Abstract

Bee venom contains a number of pharmacologically active components, including enzymes and polypeptides such as phospholipase A₂ (PLA₂) and melittin, which have been shown to exhibit therapeutic benefits, mainly via attenuation of inflammation, neurotoxicity, and nociception. The individual components of bee venom may manifest distinct biological actions and therapeutic potential. In this study, the potential mechanisms of action of PLA₂ and melittin, among different compounds purified from honey bee venom, were evaluated against Parkinson’s disease (PD). Notably, bee venom PLA₂ (bvPLA₂), but not melittin, exhibited neuroprotective activity against PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-induced behavioral deficits were also abolished after bvPLA₂ treatment, depending on the PLA₂ content. Further, bvPLA₂ administration activated regulatory T cells (Tregs) while inhibiting inflammatory T helper (Th) 1 and Th17 cells in the MPTP mouse model of PD. These results indicate that bvPLA₂, but not melittin, protected against MPTP and alleviated inflammation in PD. Thus, bvPLA₂ is a promising and effective therapeutic agent in Parkinson’s disease. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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Review

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11 pages, 817 KiB

Open AccessEditor’s ChoiceReview

From Discovery of Snake Venom Disintegrins to A Safer Therapeutic Antithrombotic Agent

by Yu-Ju Kuo, Ching-Hu Chung and Tur-Fu Huang

Toxins 2019, 11(7), 372; https://doi.org/10.3390/toxins11070372 - 26 Jun 2019

Cited by 24 | Viewed by 4446

Abstract

Snake venoms affect blood coagulation and platelet function in diverse ways. Some venom components inhibit platelet function, while other components induce platelet aggregation. Among the platelet aggregation inhibitors, disintegrins have been recognized as unique and potentially valuable tools for examining cell–matrix and cell–cell interactions and for the development of antithrombotic and antiangiogenic agents according to their anti-adhesive and anti-migration effect on tumor cells and antiangiogenesis activities. Disintegrins represent a family of low molecular weight, cysteine-rich, Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing polypeptides, which inhibit fibrinogen binding to integrin αIIbβ3 (i.e., platelet glycoprotein IIb/IIIa), as well as ligand binding to integrins αvβ3, and α5β1 expressed on cells (i.e., fibroblasts, tumor cells, and endothelial cells). This review focuses on the current efforts attained from studies using disintegrins as a tool in the field of arterial thrombosis, angiogenesis, inflammation, and tumor metastasis, and briefly describes their potential therapeutic applications and side effects in integrin-related diseases. Additionally, novel R(K)GD-containing disintegrin TMV-7 mutants are being designed as safer antithrombotics without causing thrombocytopenia and bleeding. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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15 pages, 1385 KiB

Open AccessEditor’s ChoiceReview

From Snake Venom’s Disintegrins and C-Type Lectins to Anti-Platelet Drugs

by Philip Lazarovici, Cezary Marcinkiewicz and Peter I. Lelkes

Toxins 2019, 11(5), 303; https://doi.org/10.3390/toxins11050303 - 27 May 2019

Cited by 41 | Viewed by 9138

Abstract

Snake venoms are attractive natural sources for drug discovery and development, with a number of substances either in clinical use or in research and development. These drugs were developed based on RGD-containing snake venom disintegrins, which efficiently antagonize fibrinogen activation of αIIbβ3 integrin (glycoprotein GP IIb/IIIa). Typical examples of anti-platelet drugs found in clinics are Integrilin (Eptifibatide), a heptapeptide derived from Barbourin, a protein found in the venom of the American Southeastern pygmy rattlesnake and Aggrastat (Tirofiban), a small molecule based on the structure of Echistatin, and a protein found in the venom of the saw-scaled viper. Using a similar drug discovery approach, linear and cyclic peptides containing the sequence K(R)TS derived from VP12, a C-type lectin protein found in the venom of Israeli viper venom, were used as a template to synthesize Vipegitide, a novel peptidomimetic antagonist of α2β1 integrin, with anti-platelet activity. This review focus on drug discovery of these anti-platelet agents, their indications for clinical use in acute coronary syndromes and percutaneous coronary intervention based on several clinical trials, as well as their adverse effects. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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19 pages, 3513 KiB

Open AccessEditor’s ChoiceReview

Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome

by Shira Hirsch and Joseph Tam

Toxins 2019, 11(5), 275; https://doi.org/10.3390/toxins11050275 - 15 May 2019

Cited by 26 | Viewed by 6801

Abstract

In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB₁R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB₁R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB₁R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB₁R once again. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

25 pages, 1497 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms

by Johannes A. Eble

Toxins 2019, 11(3), 136; https://doi.org/10.3390/toxins11030136 - 1 Mar 2019

Cited by 42 | Viewed by 5443

Abstract

Snake venoms contain an astounding variety of different proteins. Among them are numerous C-type lectin family members, which are grouped into classical Ca²⁺- and sugar-binding lectins and the non-sugar-binding snake venom C-type lectin-related proteins (SV-CLRPs), also called snaclecs. Both groups share the robust C-type lectin domain (CTLD) fold but differ in a long loop, which either contributes to a sugar-binding site or is expanded into a loop-swapping heterodimerization domain between two CLRP subunits. Most C-type lectin (-related) proteins assemble in ordered supramolecular complexes with a high versatility of subunit numbers and geometric arrays. Similarly versatile is their ability to inhibit or block their target molecules as well as to agonistically stimulate or antagonistically blunt a cellular reaction triggered by their target receptor. By utilizing distinct interaction sites differentially, SV-CLRPs target a plethora of molecules, such as distinct coagulation factors and receptors of platelets and endothelial cells that are involved in hemostasis, thrombus formation, inflammation and hematogenous metastasis. Because of their robust structure and their high affinity towards their clinically relevant targets, SV-CLRPs are and will potentially be valuable prototypes to develop new diagnostic and therapeutic tools in medicine, provided that the molecular mechanisms underlying their versatility are disclosed. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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34 pages, 2097 KiB

Open AccessEditor’s ChoiceReview

The Role of Toxins in the Pursuit for Novel Analgesics

by Yossi Maatuf, Matan Geron and Avi Priel

Toxins 2019, 11(2), 131; https://doi.org/10.3390/toxins11020131 - 23 Feb 2019

Cited by 30 | Viewed by 6025

Abstract

Chronic pain is a major medical issue which reduces the quality of life of millions and inflicts a significant burden on health authorities worldwide. Currently, management of chronic pain includes first-line pharmacological therapies that are inadequately effective, as in just a portion of patients pain relief is obtained. Furthermore, most analgesics in use produce severe or intolerable adverse effects that impose dose restrictions and reduce compliance. As the majority of analgesic agents act on the central nervous system (CNS), it is possible that blocking pain at its source by targeting nociceptors would prove more efficient with minimal CNS-related side effects. The development of such analgesics requires the identification of appropriate molecular targets and thorough understanding of their structural and functional features. To this end, plant and animal toxins can be employed as they affect ion channels with high potency and selectivity. Moreover, elucidation of the toxin-bound ion channel structure could generate pharmacophores for rational drug design while favorable safety and analgesic profiles could highlight toxins as leads or even as valuable therapeutic compounds themselves. Here, we discuss the use of plant and animal toxins in the characterization of peripherally expressed ion channels which are implicated in pain. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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12 pages, 567 KiB

Open AccessReview

Chlorotoxin—A Multimodal Imaging Platform for Targeting Glioma Tumors

by Gadi Cohen, Scott R. Burks and Joseph A. Frank

Toxins 2018, 10(12), 496; https://doi.org/10.3390/toxins10120496 - 26 Nov 2018

Cited by 48 | Viewed by 6585

Abstract

Chlorotoxin (CTX) is a 36-amino-acid disulfide-containing peptide derived from the venom of the scorpion Leiurus quinquestriatus. CTX alters physiology in numerous ways. It interacts with voltage gated chloride channels, Annexin-2, and matrix metalloproteinase-2 (MMP-2). CTX-based bioconjugates have been widely subjected to phase I/II clinical trials and have shown substantial promise. Many studies have demonstrated that CTX preferentially binds to neuroectodermal tumors, such as glioblastoma, without cross-reactivity to normal brain cells. With its ability to penetrate the blood-brain-barrier (BBB) and its tyrosine residue allows covalent conjugation with functional moieties, CTX is an attractive platform to explore development of diagnostic and therapeutic agents for gliomas. In this review, we outline CTX structure and its molecular targets, summarize molecular variations of CTX developed for glioma imaging, and discuss future trends and perspectives for CTX conjugates as a theranostic agent. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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12 pages, 3197 KiB

Open AccessReview

The Fever Tree: from Malaria to Neurological Diseases

by Sara Eyal

Toxins 2018, 10(12), 491; https://doi.org/10.3390/toxins10120491 - 23 Nov 2018

Cited by 26 | Viewed by 9689

Abstract

This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids’ pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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14 pages, 2596 KiB

Open AccessReview

Pharmacokinetics of Toxin-Derived Peptide Drugs

by David Stepensky

Toxins 2018, 10(11), 483; https://doi.org/10.3390/toxins10110483 - 20 Nov 2018

Cited by 22 | Viewed by 5601

Abstract

Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for protection and predation. Several toxin-derived peptides have become drugs and are used for the management of diabetes, hypertension, chronic pain, and other medical conditions. Despite the similarity in their composition (amino acids as the building blocks), toxin-derived peptide drugs have very profound differences in their structure and conformation, in their physicochemical properties (that affect solubility, stability, etc.), and subsequently in their pharmacokinetics (the processes of absorption, distribution, metabolism, and elimination following their administration to patients). This review summarizes and critically analyzes the pharmacokinetic properties of toxin-derived peptide drugs: (1) the relationship between the chemical structure, physicochemical properties, and the pharmacokinetics of the specific drugs, (2) the major pharmacokinetic properties and parameters of these drugs, and (3) the major pharmacokinetic variability factors of the individual drugs. The structural properties of toxin-derived peptides affect their pharmacokinetics and pose some limitations on their clinical use. These properties should be taken into account during the development of new toxin-derived peptide drugs, and for the efficient and safe use of the clinically approved drugs from this group in the individual patients. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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6 pages, 989 KiB

Open AccessReview

Bacterial Superantigen Toxins, CD28, and Drug Development

by Raymond Kaempfer

Toxins 2018, 10(11), 459; https://doi.org/10.3390/toxins10110459 - 6 Nov 2018

Cited by 13 | Viewed by 5714

Abstract

During severe bacterial infections, death and disease are often caused by an overly strong immune response of the human host. Acute toxic shock is induced by superantigen toxins, a diverse set of proteins secreted by Gram-positive staphylococcal and streptococcal bacterial strains that overstimulate the inflammatory response by orders of magnitude. The need to protect from superantigen toxins led to our discovery that in addition to the well-known MHC class II and T cell receptors, the principal costimulatory receptor, CD28, and its constitutively expressed coligand, B7-2 (CD86), previously thought to have only costimulatory function, are actually critical superantigen receptors. Binding of the superantigen into the homodimer interfaces of these costimulatory receptors greatly enhances B7-2/CD28 engagement, leading to excessive pro-inflammatory signaling. This finding led to the design of short receptor dimer interface mimetic peptides that block the binding of superantigen and thus protect from death. It then turned out that such a peptide will protect also from Gram-negative bacterial infection and from polymicrobial sepsis. One such CD28 mimetic peptide is advancing in a Phase 3 clinical trial to protect from lethal wound infections by flesh-eating bacteria. These host-oriented therapeutics target the human immune system itself, rendering pathogens less likely to become resistant. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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24 pages, 1157 KiB

Open AccessReview

Recombinant and Chimeric Disintegrins in Preclinical Research

by Victor David, Barbara Barbosa Succar, João Alfredo De Moraes, Roberta Ferreira Gomes Saldanha-Gama, Christina Barja-Fidalgo and Russolina Benedeta Zingali

Toxins 2018, 10(8), 321; https://doi.org/10.3390/toxins10080321 - 7 Aug 2018

Cited by 21 | Viewed by 5464

Abstract

Disintegrins are a family of small cysteine-rich peptides, found in a wide variety of snake venoms of different phylogenetic origin. These peptides selectively bind to integrins, which are heterodimeric adhesion receptors that play a fundamental role in the regulation of many physiological and pathological processes, such as hemostasis and tumor metastasis. Most disintegrins interact with integrins through the RGD (Arg-Gly-Asp) sequence loop, resulting in an active site that modulates the integrin activity. Some variations in the tripeptide sequence and the variability in its neighborhood result in a different specificity or affinity toward integrin receptors from platelets, tumor cells or neutrophils. Recombinant forms of these proteins are obtained mainly through Escherichia coli, which is the most common host used for heterologous expression. Advances in the study of the structure-activity relationship and importance of some regions of the molecule, especially the hairpin loop and the C-terminus, rely on approaches such as site-directed mutagenesis and the design and expression of chimeric peptides. This review provides highlights of the biological relevance and contribution of recombinant disintegrins to the understanding of their binding specificity, biological activities and therapeutic potential. The biological and pharmacological relevance on the newest discoveries about this family of integrin-binding proteins are discussed. Full article

(This article belongs to the Special Issue From Toxins to Drugs)

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