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Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin.

ABSTRACT: The current trend of using recombinant antibody fragments in research to develop novel antidotes against scorpion stings has achieved excellent results. The polyclonal character of commercial antivenoms, obtained through the immunization of animals and which contain several neutralizing antibodies that recognize different epitopes on the toxins, guarantees the neutralization of the venoms. To avoid the use of animals, we aimed to develop an equivalent recombinant antivenom composed of a few neutralizing single chain antibody fragments (scFvs) that bind to two different epitopes on the scorpion toxins. In this study, we obtained scFv RU1 derived from scFv C1. RU1 showed a good capacity to neutralize the Cn2 toxin and whole venom of the scorpion Centruroides noxius. Previously, we had produced scFv LR, obtained from a different parental fragment (scFv 3F). LR also showed a similar neutralizing capacity. The simultaneous administration of both scFvs resulted in improved protection, which was translated as a rapid recovery of previously poisoned animals. The crystallographic structure of the ternary complex scFv LR-Cn2-scFv RU1 allowed us to identify the areas of interaction of both scFvs with the toxin, which correspond to non-overlapping sites. The epitope recognized by scFv RU1 seems to be related to a greater efficiency in the neutralization of the whole venom. In addition, the structural analysis of the complex helped us to explain the cross-reactivity of these scFvs and how they neutralize the venom.

SUBMITTER: Riano-Umbarila L

PROVIDER: S-EPMC4722445 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin.

Riaño-Umbarila Lidia L Ledezma-Candanoza Luis M LM Serrano-Posada Hugo H Fernández-Taboada Guillermo G Olamendi-Portugal Timoteo T Rojas-Trejo Sonia S Gómez-Ramírez Ilse V IV Rudiño-Piñera Enrique E Possani Lourival D LD Becerril Baltazar B

The Journal of biological chemistry 20151120 4

The current trend of using recombinant antibody fragments in research to develop novel antidotes against scorpion stings has achieved excellent results. The polyclonal character of commercial antivenoms, obtained through the immunization of animals and which contain several neutralizing antibodies that recognize different epitopes on the toxins, guarantees the neutralization of the venoms. To avoid the use of animals, we aimed to develop an equivalent recombinant antivenom composed of a few neut ...[more]

PMID: 26589800

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Project description:Scorpion venoms have been studied for decades, leading to the identification of hundreds of different toxins with medical and pharmacological implications. However, little emphasis has been given to the description of these arthropods from cellular and evolutionary perspectives. In this report, we describe a transcriptomic analysis of the Mexican scorpion Centruroides noxius Hoffmann, performed with a pyrosequencing platform. Three independent sequencing experiments were carried out, each including three different cDNA libraries constructed from RNA extracted from the whole body of the scorpion after telson removal, and from the venom gland before and after venom extraction. Over three million reads were obtained and assembled in almost 19000 isogroups. Within the telson-specific sequences, 72 isogroups (0.4% of total unique transcripts) were found to be similar to toxins previously reported in other scorpion species, spiders and sea anemones. The annotation pipeline also revealed the presence of important elements of the small non-coding RNA processing machinery, as well as microRNA candidates. A phylogenomic analysis of concatenated essential genes evidenced differential evolution rates in this species, particularly in ribosomal proteins and proteasome components. Additionally, statistical comparison of transcript abundance before and after venom extraction showed that 3% and 2% of the assembled isogroups had higher expression levels in the active and replenishing gland, respectively. Thus, our sequencing and annotation strategies provide a general view of the cellular and molecular processes that take place in these arthropods, allowed the discovery of new pharmacological and biotechnological targets and uncovered several regulatory and metabolic responses behind the assembly of the scorpion venom. The results obtained in this report represent the first high-throughput study that thoroughly describes the universe of genes that are expressed in the scorpion Centruroides noxius Hoffmann, a highly relevant organism from medical and evolutionary perspectives.

Dataset Information

Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin.

Publications

Optimal Neutralization of Centruroides noxius Venom Is Understood through a Structural Complex between Two Antibody Fragments and the Cn2 Toxin.

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