Importance of the Cysteine-Rich Domain of Snake Venom Prothrombin Activators: Insights Gained from Synthetic Neutralizing Antibodies

Misson Mindrebo, Laetitia E., Mindrebo, Jeffrey T., Tran, Quoc, Wilkinson, Mark ORCID: https://orcid.org/0000-0003-3109-6888, Smith, Jessica M., Verma, Megan, Casewell, Nicholas ORCID: https://orcid.org/0000-0002-8035-4719, Lander, Gabriel C. and Jardine, Joseph G. (2024) 'Importance of the Cysteine-Rich Domain of Snake Venom Prothrombin Activators: Insights Gained from Synthetic Neutralizing Antibodies'. Toxins, Vol 16, Issue 8, p. 361.

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Abstract

Snake venoms are cocktails of biologically active molecules that have evolved to immobilize prey, but can also induce a severe pathology in humans that are bitten. While animal-derived polyclonal antivenoms are the primary treatment for snakebites, they often have limitations in efficacy and can cause severe adverse side effects. Building on recent efforts to develop improved antivenoms, notably through monoclonal antibodies, requires a comprehensive understanding of venom toxins. Among these toxins, snake venom metalloproteinases (SVMPs) play a pivotal role, particularly in viper envenomation, causing tissue damage, hemorrhage and coagulation disruption. One of the current challenges in the development of neutralizing monoclonal antibodies against SVMPs is the large size of the protein and the lack of existing knowledge of neutralizing epitopes. Here, we screened a synthetic human antibody library to isolate monoclonal antibodies against an SVMP from saw-scaled viper (genus Echis) venom. Upon characterization, several antibodies were identified that effectively blocked SVMP-mediated prothrombin activation. Cryo-electron microscopy revealed the structural basis of antibody-mediated neutralization, pinpointing the non-catalytic cysteine-rich domain of SVMPs as a crucial target. These findings emphasize the importance of understanding the molecular mechanisms of SVMPs to counter their toxic effects, thus advancing the development of more effective antivenoms.

Item Type:	Article
Additional Information:	** Article version: VoR ** From Crossref journal articles via Jisc Publications Router ** History: epub 15-08-2024; issued 15-08-2024. ** Licence for VoR version of this article starting on 15-08-2024: https://creativecommons.org/licenses/by/4.0/
Subjects:	WC Communicable Diseases > Tropical and Parasitic Diseases > WC 680 Tropical diseases (General) WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.3390/toxins16080361
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	05 Sep 2024 10:12
Last Modified:	05 Sep 2024 10:14
URI:	https://archive.lstmed.ac.uk/id/eprint/25214

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