Investigation of the reactivation kinetics of a large series of bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase

Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for postexposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre-and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE.

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“…; Winter et al . ), but none of them have the broad‐spectrum qualification required for further development.…”

Section: Post‐exposure Treatmentmentioning

confidence: 99%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

123

105

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“…52,53 The limited effectiveness of these established oximes has resulted in continuing research to develop several more novel oximes for the reactivation of OP-inhibited AChE. 55 Table 2 shows examples of several newly developed oximes in attempt to improve the antidotes efficacy. For example, the oximes K 027 and K 048 are currently being tested in many countries because of their extraordinary potency and low toxicity.…”

Section: Organophosphorus Nerve Agentsmentioning

confidence: 99%

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

et al. 2020

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“…The reactivation of the OP-inhibited HssAChE by pyridinium-aldoxime-based drugs has been the most relevant action for therapy against lethal OP poisoning [13,15,16] since 1956, when the 2-pyridinium methyl aldoxime (known as pralidoxime or 2-PAM) was first used in therapy against intoxication by parathion in Japan [17]. Today, the most accepted mechanism of action of such drugs [12,15], which are all 2-PAM derivatives [18], is the nucleophile attack on the Ser203-OP adduct, followed by the removal of the phosphate moiety from the enzyme's active site [13,15,19].…”

Section: Introductionmentioning

confidence: 99%

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

Silva¹,

Pereira

LaPlante

et al. 2020

Biomolecules

Self Cite

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In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition–elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

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Investigation of the reactivation kinetics of a large series of bispyridinium oximes with organophosphate-inhibited human acetylcholinesterase

Cited by 44 publications

References 29 publications

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

Reactivation of VX-Inhibited Human Acetylcholinesterase by Deprotonated Pralidoxime. A Complementary Quantum Mechanical Study

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