Abstract
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.
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Acknowledgements
The authors are grateful to the Military Institute of Engineering (IME), Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army Technological Center (CTEx), Federal University of Lavras (for software licenses), University of Hradec Kralové and the CQDM SynergiQc grant.
Funding
This research was funded by the Brazilian agencies Conselho Nacional de Pesquisa (CNPq), grant no. 308225/2018–0; Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), grant no. E-02/202.961/2017; IFES—PRPPG, grant number 10/2019 (Productivity Researcher Program PPP); and FAPES, grant number 03/2020-2020-WMT5F. The authors are also grateful to the Excelence project PrF UHK 2217/2022-2023 for financial support.
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Santos, M.C., Botelho, F.D., Gonçalves, A.S. et al. Are the current commercially available oximes capable of reactivating acetylcholinesterase inhibited by the nerve agents of the A-series?. Arch Toxicol 96, 2559–2572 (2022). https://doi.org/10.1007/s00204-022-03316-z
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DOI: https://doi.org/10.1007/s00204-022-03316-z