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Are the current commercially available oximes capable of reactivating acetylcholinesterase inhibited by the nerve agents of the A-series?

Santos, Marcelo C, Botelho, Fernanda D, Gonçalves, Arlan S, Kitagawa, Daniel A S, Borges, Caio V N, Carvalho-Silva, Taynara, Bernardo, Leandro B, Ferreira, Cintia N, Rodrigues, Rafael B, Ferreira Neto, Denise C, Nepovimova, Eugenie, Kuca, Kamil, Laplante, Steven ORCID: https://orcid.org/0000-0003-2835-5789, Lima, Antoni L S, Franca, Tanos Celmar Costa et Cavalcante, Samir F A (2022). Are the current commercially available oximes capable of reactivating acetylcholinesterase inhibited by the nerve agents of the A-series? Archives of Toxicology , vol. ahead . DOI: 10.1007/s00204-022-03316-z. (Sous Presse)

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Résumé

The misuse of novichok agents in assassination attempts has been reported in the international media since 2018. These relatively new class of neurotoxic agents is claimed to be more toxic than the agents of the G and V series and so far, there is no report yet in literature about potential antidotes against them. To shed some light into this issue, we report here the design and synthesis of NTMGMP, a surrogate of A-242 and also the first surrogate of a novichok agent useful for experimental evaluation of antidotes. Furthermore, the efficiency of the current commercial oximes to reactivate NTMGMP-inhibited acetylcholinesterase (AChE) was evaluated. The Ellman test was used to confirm the complete inhibition of AChE, and to compare the subsequent rates of reactivation in vitro as well as to evaluate aging. In parallel, molecular docking, molecular dynamics and MM-PBSA studies were performed on a computational model of the human AChE (HssAChE)/NTMGMP complex to assess the reactivation performances of the commercial oximes in silico. Experimental and theoretical studies matched the exact hierarchy of efficiency and pointed to trimedoxime as the most promising commercial oxime for reactivation of AChE inhibited by A-242. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Type de document: Article
Mots-clés libres: A-242; AChE; Commercial reactivators; Novichoks; Surrogates
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 10 juill. 2022 14:06
Dernière modification: 10 juill. 2022 14:06
URI: https://espace.inrs.ca/id/eprint/12789

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