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14 pages, 1233 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Vipera berus berus Venom from Russia: Venomics, Bioactivities and Preclinical Assessment of Microgen Antivenom

by Ruslan I. Al-Shekhadat, Ksenia S. Lopushanskaya, Álvaro Segura, José María Gutiérrez, Juan J. Calvete and Davinia Pla

Toxins 2019, 11(2), 90; https://doi.org/10.3390/toxins11020090 - 1 Feb 2019

Cited by 29 | Viewed by 8606

Abstract

The common European adder, Vipera berus berus, is a medically relevant species, which is widely distributed in Russia and thus, is responsible for most snakebite accidents in Russia. We have investigated the toxic and enzymatic activities and have determined the proteomic composition [...] Read more.

The common European adder, Vipera berus berus, is a medically relevant species, which is widely distributed in Russia and thus, is responsible for most snakebite accidents in Russia. We have investigated the toxic and enzymatic activities and have determined the proteomic composition of its venom. Phospholipases A₂ (PLA₂, 25.3% of the venom proteome), serine proteinases (SVSP, 16.2%), metalloproteinases (SVMP, 17.2%), vasoactive peptides (bradykinin-potentiating peptides (BPPs), 9.5% and C-type natriuretic peptides (C-NAP, 7.8%), cysteine-rich secretory protein (CRISP, 8%) and L-amino acid oxidase (LAO, 7.3%) represent the major toxin classes found in V. b. berus (Russia) venom. This study was also designed to assess the in vivo and in vitro preclinical efficacy of the Russian Microgen antivenom in neutralizing the main effects of V. b. berus venom. The results show that this antivenom is capable of neutralizing the lethal, hemorrhagic and PLA₂ activities. Third-generation antivenomics was applied to quantify the toxin-recognition landscape and the maximal binding capacity of the antivenom for each component of the venom. The antivenomics analysis revealed that 6.24% of the anti-V. b. berus F(ab’)₂ molecules fraction are toxin-binding antibodies, 60% of which represent clinically relevant antivenom molecules. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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16 pages, 2607 KiB

Open AccessArticle

Effects of Two Fractions of Swietenia macrophylla and Catechin on Muscle Damage Induced by Bothrops Venom and PLA₂

by Silvia Posada Arias, Berardo de Jesús Rodríguez, Tatiana Lobo-Echeverri, Raphael Shezaro Ramos, Stephen Hyslop and Vitelbina Núñez Rangel

Toxins 2019, 11(1), 40; https://doi.org/10.3390/toxins11010040 - 14 Jan 2019

Cited by 6 | Viewed by 3339

Abstract

Plant natural products can attenuate the myonecrosis caused by Bothrops snake venom and their phospholipases A₂ (PLA₂). In this study, we evaluated the effects of two fractions (F4 and F6) from Swietenia macrophylla and purified catechin on the muscle damage [...] Read more.

Plant natural products can attenuate the myonecrosis caused by Bothrops snake venom and their phospholipases A₂ (PLA₂). In this study, we evaluated the effects of two fractions (F4 and F6) from Swietenia macrophylla and purified catechin on the muscle damage caused by a myotoxic PLA₂ from Colombian Bothrops asper venom (BaColPLA₂) in mice and by Bothrops marmoratus venom from Brazil in mouse phrenic nerve-diaphragm muscle (PND) preparations in vitro. Male mice were injected with PLA₂ (50 µg) in the absence or presence of F4, F6, and catechin, in the gastrocnemius muscle and then killed 3, 7, 14, and 28 h later for histopathological analysis of myonecrosis, leukocyte infiltration, and the presence of collagen. Fractions F4 and F6 (500 µg) and catechin (90 µg) significantly reduced the extent of necrosis at all-time intervals. These two fractions and catechin also attenuated the leukocyte infiltration on day 3, as did catechin on day 14. There was medium-to-moderate collagen deposition in all groups up to day 7, but greater deposition on days 14 and 28 in the presence of F6 and catechin. Bothrops marmoratus venom (100 µg/mL) caused slight (~25%) muscle facilitation after 10 min and weak neuromuscular blockade (~64% decrease in contractile activity after a 120-min incubation). Pre-incubation of venom with F4 or F6 abolished the facilitation, whereas catechin, which was itself facilitatory, did not. All three fractions attenuated the venom-induced decrease in muscle contractions. These findings indicate that fractions and catechin from S. macrophylla can reduce the muscle damage caused by Bothrops venom and PLA₂. These fractions or their components could be useful for treating venom-induced local damage. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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17 pages, 2425 KiB

Open AccessEditor’s ChoiceArticle

Generation of a Broadly Cross-Neutralizing Antibody Fragment against Several Mexican Scorpion Venoms

by Lidia Riaño-Umbarila, Ilse V. Gómez-Ramírez, Luis M. Ledezma-Candanoza, Timoteo Olamendi-Portugal, Everardo Remi Rodríguez-Rodríguez, Guillermo Fernández-Taboada, Lourival D. Possani and Baltazar Becerril

Toxins 2019, 11(1), 32; https://doi.org/10.3390/toxins11010032 - 10 Jan 2019

Cited by 24 | Viewed by 4198

Abstract

The recombinant antibody fragments generated against the toxic components of scorpion venoms are considered a promising alternative for obtaining new antivenoms for therapy. Using directed evolution and site-directed mutagenesis, it was possible to generate a human single-chain antibody fragment with a broad cross-reactivity [...] Read more.

The recombinant antibody fragments generated against the toxic components of scorpion venoms are considered a promising alternative for obtaining new antivenoms for therapy. Using directed evolution and site-directed mutagenesis, it was possible to generate a human single-chain antibody fragment with a broad cross-reactivity that retained recognition for its original antigen. This variant is the first antibody fragment that neutralizes the effect of an estimated 13 neurotoxins present in the venom of nine species of Mexican scorpions. This single antibody fragment showed the properties of a polyvalent antivenom. These results represent a significant advance in the development of new antivenoms against scorpion stings, since the number of components would be minimized due to their broad cross-neutralization capacity, while at the same time bypassing animal immunization. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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15 pages, 15530 KiB

Open AccessArticle

Antivenom Production against Bothrops jararaca and Bothrops erythromelas Snake Venoms Using Cross-Linked Chitosan Nanoparticles as an Immunoadjuvant

by Karla Samara Rocha Soares, Fiamma Gláucia-Silva, Alessandra Daniele-Silva, Manoela Torres-Rêgo, Nathália Kelly de Araújo, Yamara Arruda Silva de Menezes, Igor Zumba Damasceno, Denise Vilarinho Tambourgi, Arnóbio Antônio Da Silva-Júnior and Matheus De Freitas Fernandes-Pedrosa

Toxins 2018, 10(4), 158; https://doi.org/10.3390/toxins10040158 - 16 Apr 2018

Cited by 18 | Viewed by 5643

Abstract

In Brazil, envenomation by snakes of the genus Bothrops is clinically relevant, particularly for the species Bothrops jararaca and B. erythromelas. The most effective treatment for envenomation by snakes is the administration of antivenoms associated with adjuvants. Novel adjuvants are required to [...] Read more.

In Brazil, envenomation by snakes of the genus Bothrops is clinically relevant, particularly for the species Bothrops jararaca and B. erythromelas. The most effective treatment for envenomation by snakes is the administration of antivenoms associated with adjuvants. Novel adjuvants are required to reduce side effects and maximize the efficiency of conventional serum and vaccine formulations. The polymer chitosan has been shown to have immunoadjuvant properties, and it has been used as a platform for delivery systems. In this context, we evaluated the potential immunoadjuvant properties of chitosan nanoparticles (CNPs) loaded with B. jararaca and B. erythromelas venoms in the production of sera against these venoms. Stable CNPs were obtained by ionic gelation, and mice were immunized subcutaneously for 6 weeks with 100 µL of each snake venom at concentrations of 5.0 or 10.0% (w/w), encapsulated in CNPs or associated with aluminium hydroxide (AH). The evaluation of protein interactions with the CNPs revealed their ability to induce antibody levels equivalent to those of AH, even with smaller doses of antigen. In addition, the CNPs were less inflammatory due to their modified release of proteins. CNPs provide a promising approach for peptide/protein delivery from snake venom and will be useful for new vaccines. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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20 pages, 39312 KiB

Open AccessFeature PaperArticle

Camelid Single-Domain Antibodies (VHHs) against Crotoxin: A Basis for Developing Modular Building Blocks for the Enhancement of Treatment or Diagnosis of Crotalic Envenoming

by Marcos B. Luiz, Soraya S. Pereira, Nidiane D. R. Prado, Naan R. Gonçalves, Anderson M. Kayano, Leandro S. Moreira-Dill, Juliana C. Sobrinho, Fernando B. Zanchi, André L. Fuly, Cleberson F. Fernandes, Juliana P. Zuliani, Andreimar M. Soares, Rodrigo G. Stabeli and Carla F. C. Fernandes

Toxins 2018, 10(4), 142; https://doi.org/10.3390/toxins10040142 - 29 Mar 2018

Cited by 23 | Viewed by 6319

Abstract

Toxic effects triggered by crotalic envenoming are mainly related to crotoxin (CTX), composed of a phospholipase A₂ (CB) and a subunit with no toxic activity (CA). Camelids produce immunoglobulins G devoid of light chains, in which the antigen recognition domain is called [...] Read more.

Toxic effects triggered by crotalic envenoming are mainly related to crotoxin (CTX), composed of a phospholipase A₂ (CB) and a subunit with no toxic activity (CA). Camelids produce immunoglobulins G devoid of light chains, in which the antigen recognition domain is called VHH. Given their unique characteristics, VHHs were selected using Phage Display against CTX from Crotalus durissus terrificus. After three rounds of biopanning, four sequence profiles for CB (KF498602, KF498603, KF498604, and KF498605) and one for CA (KF498606) were revealed. All clones presented the VHH hallmark in FR2 and a long CDR3, with the exception of KF498606. After expressing pET22b-VHHs in E. coli, approximately 2 to 6 mg of protein per liter of culture were obtained. When tested for cross-reactivity, VHHs presented specificity for the Crotalus genus and were capable of recognizing CB through Western blot. KF498602 and KF498604 showed thermostability, and displayed affinity constants for CTX in the micro or nanomolar range. They inhibited in vitro CTX PLA₂ activity, and CB cytotoxicity. Furthermore, KF498604 inhibited the CTX-induced myotoxicity in mice by 78.8%. Molecular docking revealed that KF498604 interacts with the CA–CB interface of CTX, seeming to block substrate access. Selected VHHs may be alternatives for the crotalic envenoming treatment. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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Review

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19 pages, 2427 KiB

Open AccessFeature PaperReview

Antibody Cross-Reactivity in Antivenom Research

by Line Ledsgaard, Timothy P. Jenkins, Kristian Davidsen, Kamille Elvstrøm Krause, Andrea Martos-Esteban, Mikael Engmark, Mikael Rørdam Andersen, Ole Lund and Andreas Hougaard Laustsen

Toxins 2018, 10(10), 393; https://doi.org/10.3390/toxins10100393 - 27 Sep 2018

Cited by 40 | Viewed by 8247

Abstract

Antivenom cross-reactivity has been investigated for decades to determine which antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization [...] Read more.

Antivenom cross-reactivity has been investigated for decades to determine which antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization studies. In recent years, new methods for determination of cross-reactivity have emerged, including surface plasmon resonance, antivenomics, and high-density peptide microarray technology. Antivenomics involves a top-down assessment of the toxin-binding capacities of antivenoms, whereas high-density peptide microarray technology may be harnessed to provide in-depth knowledge on which toxin epitopes are recognized by antivenoms. This review provides an overview of both the classical and new methods used to investigate antivenom cross-reactivity, the advantages and disadvantages of each method, and examples of studies using the methods. A special focus is given to antivenomics and high-density peptide microarray technology as these high-throughput methods have recently been introduced in this field and may enable more detailed assessments of antivenom cross-reactivity. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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13 pages, 1867 KiB

Open AccessReview

Current Advances in Immunological Studies on the Vespidae Venom Antigen 5: Therapeutic and Prophylaxis to Hypersensitivity Responses

by Murilo Luiz Bazon, Lais Helena Silveira, Patricia Ucelli Simioni and Márcia Regina Brochetto-Braga

Toxins 2018, 10(8), 305; https://doi.org/10.3390/toxins10080305 - 24 Jul 2018

Cited by 11 | Viewed by 5059

Abstract

Although systemic reactions caused by allergenic proteins present in venoms affect a small part of the world population, Hymenoptera stings are among the main causes of immediate hypersensitivity responses, with risk of anaphylactic shock. In the attempt to obtain therapeutic treatments and prophylaxis [...] Read more.

Although systemic reactions caused by allergenic proteins present in venoms affect a small part of the world population, Hymenoptera stings are among the main causes of immediate hypersensitivity responses, with risk of anaphylactic shock. In the attempt to obtain therapeutic treatments and prophylaxis to hypersensitivity responses, interest in the molecular characterization of these allergens has grown in the scientific community due to the promising results obtained in immunological and clinical studies. The present review provides an update on the knowledge regarding the immune response and the therapeutic potential of Antigen 5 derived from Hymenoptera venom. The results confirm that the identification and topology of epitopes, associated with molecular regions that interact with antibodies, are crucial to the improvement of hypersensitivity diagnostic methods. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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15 pages, 4086 KiB

Open AccessFeature PaperReview

Basics of Antibody Phage Display Technology

by Line Ledsgaard, Mogens Kilstrup, Aneesh Karatt-Vellatt, John McCafferty and Andreas H. Laustsen

Toxins 2018, 10(6), 236; https://doi.org/10.3390/toxins10060236 - 9 Jun 2018

Cited by 162 | Viewed by 31183

Abstract

Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of [...] Read more.

Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of the M13 phage and the basics of phage display technology are presented together with important factors influencing the success rates of phage display experiments. Moreover, the pros and cons of different antigen display methods and the use of naïve versus immunized phage display antibody libraries is discussed, and selected examples from the field of antivenom research are highlighted. This review thus provides in-depth knowledge on the principles and use of phage display technology with a special focus on discovery of antibodies that target animal toxins. Full article

(This article belongs to the Special Issue Discovery of Antibodies and Novel Antivenoms against Envenoming)

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