Novichok nerve agent poisoning

Steindl, David; Boehmerle, Wolfgang; Körner, Roland; Praeger, Damaris; Haug, Marcel; Nee, Jens; Schreiber, Adrian; Scheibe, Franziska; Demin, Katharina; Jacoby, Philipp; Tauber, Rudolf; Härtwig, Sven; Endres, Matthias; Eckardt, Kai‐Uwe

doi:10.1016/s0140-6736(20)32644-1

Cited by 102 publications

(82 citation statements)

References 15 publications

(17 reference statements)

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“…Organophosphorus (OP) nerve agents are extremely hazardous compounds that were repeatedly used in military conflicts and by terrorists. Recent nerve agent attacks with sarin in Syria since 2013, assassinations with VX in Malaysia 2017 and with Novichok agents in UK 2018 and Russia 2020 underline the ongoing threat and the necessity for effective medical countermeasures (Costanzi et al 2018;John et al 2018;Steindl et al 2021).…”

Section: Introductionmentioning

confidence: 99%

Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

et al. 2021

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Highly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay. In addition, we studied one BdPTE version that was fused with structurally disordered PAS polypeptides to enable delayed plasma clearance and one bispecific BdPTE with broadened substrate spectrum composed of two functionally distinct subunits connected by a PAS linker. Measured kcat/KM values were as high as 6.5 and 1.5 × 108 M−1 min−1 with G- and V-agents, respectively. Furthermore, the stereoselective degradation of VX enantiomers by the PASylated BdPTE-4 and the bispecific BdPTE-7 were investigated by chiral LC–MS/MS, resulting in a several fold faster hydrolysis of the more toxic P(−) VX stereoisomer compared to P(+) VX. In conclusion, the newly developed enzymes BdPTE-4 and BdPTE-7 have shown high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(−) VX enantiomer in vitro and offer promise for use as bioscavengers in vivo.

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Section: Introductionmentioning

confidence: 99%

Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

et al. 2021

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“…OPs present a large group of chemicals used as pesticides, flame retardants, etc., and misused as nerve agents. Their non-selective species toxicity can cause severe biological effects to humans [1,2]. The related enzyme butyrylcholinesterase (BChE) is also involved in the regulation of the cholinergic system as a backup to AChE in hydrolyzing the neurotransmitter acetylcholine (ACh) in neurological disorders [3].…”

Section: Introductionmentioning

confidence: 99%

New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

et al. 2021

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The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti- and trans,syn-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.

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“…The lessons identified here have since helped international colleagues achieve a positive outcome in a very similar case. 13…”

Section: Summary Of Key Lessons Learnedmentioning

confidence: 99%

Chemical, biological, radiological, and nuclear mass casualty medicine: a review of lessons from the Salisbury and Amesbury Novichok nerve agent incidents

Haslam

Russell

Hill

et al. 2022

British Journal of Anaesthesia

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Novichok nerve agent poisoning

Cited by 102 publications

References 15 publications

Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

Chemical, biological, radiological, and nuclear mass casualty medicine: a review of lessons from the Salisbury and Amesbury Novichok nerve agent incidents

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