Reactivation of VX-inhibited AChE by novel oximes having two oxygen atoms in the linker

Kuča, Kamil; Cabal, Jiřı́; Jun, Daniel; Musílek, Kamil; Soukup, Ondřej; Pohanka, Miroslav; Pejchal, Jaroslav; Oh, Kyung-Ae; Yang, Garp Yeol; Jung, Young‐Sik

doi:10.1016/j.etap.2010.03.011

Cited by 7 publications

(16 citation statements)

References 27 publications

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“…HuAChE or huBChE were treated with F-VX-surrogate (from 10 to 160 nM) to > 95% inhibition and the recovery of enzyme activity measured following dilution to halt further inhibition or possible re-inhibition. The spontaneous reactivation rate constants ( k r ) for were9.31 × 10 −5 min −1 (t ½ = 124 h; HuAChE) and 1.13 × 10 −4 min −1 (t ½ = 102 h; HuBChE), which data is in general agreement with k r rates found for VX and the p -nitrophenoxy VX surrogates (Albuquerque et al, 2006; Coban et al, 2016; Kuca et al, 2010a; Sidell and Groff, 1974). The data implies that ChE-OP(O)(CH 3 )(OCH 2 CH 2 F) adducts are stable and likely measurable in vivo as the corresponding [ 18 F]containing OP-AChE adduct over the lifetime of the tracer, although the lack of restoration of enzyme activity cannot be attributed solely to the ChE-OP(O)(CH 3 )(OCH 2 CH 2 F) adduct.…”

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Msupporting

confidence: 81%

“…Spontaneous reactivation is a process whereby formation of the OP-cholinesterase adduct is reversed by scission of the phosphoserine bond without the aid of reactivating agents (Bajgar, 2004; Barthold and Schier, 2005; Fukuto, 1990b; Holstege et al, 1997; Kuca et al, 2010a; Taylor, 2018; Worek et al, 2008) and part or all of the catalytic activity is restored. Typically, OP-ChE adducts containing P-OMe or P-OEt groups undergo spontaneous reactivation in a few minutes to hours (Morita, 1995; Worek et al, 2008) whereas OP-ChE adducts with branched esters like P-OiPr or P-OCH(Me)C(Me) 3 reactivate slowly and/or undergo an alternate mechanism known as aging.…”

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

“…Spontaneous and oxime-mediated reactivation rates were comparable for both HuAChE and HuBChE and expectedly the oxime-mediated rates were 100- to 250-fold faster than spontaneous rates. Rate accelerations of 100-fold when using oximes for VX-inhibited cholinesterases have been reported (Forsberg and Puu, 1984; Kuca et al, 2010a; Kuca et al, 2010b). There was little difference in the oxime-mediated reactivation rates found at 30 min and 18 h, and in general, mammalian enzyme inactivated at > 95% of its′ initial velocity fully recovered activity.…”

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

“…For example, OP-AChE adducts formed from CWAs do not reactivate to the levels observed from F-VX surrogate due to a competing aging process. The nerve agent VX is an exception (Sidell and Groff, 1974) that yields an (EtO)(Me)P(O)-AChE adduct that is largely reactivatable but still undergoes some aging (Dorandeu et al, 2008; Kuca et al, 2010a; Meek et al, 2012; Shih et al, 2010a).…”

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

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Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

Thompson

Gerdes

VanBrocklin

2020

Neurobiology of Disease

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There is a unique in vivo interplay involving the mechanism of inactivation of acetylcholinesterase (AChE) by toxic organophosphorus (OP) compounds and the restoration of AChE activity by oxime antidotes. OP compounds form covalent adducts to this critical enzyme target and oximes are introduced to directly displace the OP from AChE. For the most part, the in vivo inactivation of AChE leading to neurotoxicity and antidote-based therapeutic reversal of this mechanism are well understood, however, these molecular-level events have not been evaluated by dynamic imaging in living systems at millimeter resolution. A deeper understanding of these critically, time-dependent mechanisms is needed to develop new countermeasures. To address this void and to help accelerate the development of new countermeasures, positron-emission tomography (PET) has been investigated as a unique opportunity to create platform technologies to directly examine the interdependent toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic features of OPs and oximes in real time within live animals. This review will cover two first-in-class PET tracers representing an OP and an oxime antidote, including their preparation, requisite pharmacologic investigations, mechanistic interpretations, bio-distribution and imaging.

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Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Msupporting

confidence: 81%

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

Section: F-vx Surrogate: O-(2-[18f]fluoroethyl)-o-(p-nitrophenyl) Mmentioning

confidence: 99%

See 2 more Smart Citations

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

Thompson

Gerdes

VanBrocklin

2020

Neurobiology of Disease

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“…2,4,11,13,17,22,26,48–50 2-PAM (pralidoxime) is the only FDA-approved countermeasure for OP chemical agent exposure for use in the US. The reaction of the ChE-1 inhibitor complex with 2-PAM was evaluated using the same concentrations of inhibitor 1 as that used for spontaneous reactivation.…”

Section: Resultsmentioning

confidence: 99%

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Chao

Ahmed

Gerdes

et al. 2016

Chem. Res. Toxicol.

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The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1 is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([18F]1) of acetylcholinesterase (AChE). In rats, [18F]1 localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH3)(18FCH2CH2O)P(O)-AChE adduct (ChE-1). Characterization of this adduct would define the inhibition mechanism and subsequent postinhibitory pathways and reactivation rates. To validate this adduct, the stability (hydrolysis) of 1 and ChE-1 reactivation rates were determined. Base hydrolysis of 1 yields p-nitrophenol and (CH3) (FCH2CH2O)P(O)OH with pseudo first order rate constants (kobsd) at pH 7.4 (PBS) of 3.25 × 10−4 min−1 (t1/2 = 35.5 h) at 25 °C and 8.70 × 10−4 min−1 (t1/2 = 13.3 h) at 37 °C. Compound 1 was a potent inhibitor of human acetylcholinesterase (HuAChE; ki = 7.5 × 105 M−1 min−1), electric eel acetylcholinesterase (EEAChE) (ki = 3.0 × 106 M−1 min−1), and human serum butyrylcholinesterase (HuBChE; 1.95 × 105 M−1 min−1). Spontaneous and oxime-mediated reactivation rates for the (CH3) (FCH2CH2O)P(O)-serine ChE adducts using 2-PAM (10 μM) were (a) HuAChE 8.8 × 10−5 min−1 (t1/2 = 131.2 h) and 2.41 × 10−2 min−1 (t1/2 = 0.48 h), (b) EEAChE 9.32 × 10−3 min−1 (t1/2 = 1.24 h) and 3.33 × 10−2 min−1 (t1/2 = 0.35 h), and (c) HuBChE 1.16 × 10−4 min−1 (t1/2 = 99.6 h) and 4.19 × 10−2 min−1 (t1/2 = 0.27 h). All ChE-1 adducts undergo rapid and near complete restoration of enzyme activity following addition of 2-PAM (30 min), and no aging was observed for either reactivation process. The fast reactivation rates and absence of aging of ChE-1 adducts are explained on the basis of the electron-withdrawing fluorine group that favors the nucleophilic reactivation processes but disfavors cation-based dealkylation aging mechanisms. Therefore, the likely fate of radiolabeled compound 1 in vivo is the formation of (CH3)(FCH2CH2O)P(O)-serine adducts and monoacid (CH3)(FCH2CH2O)P(O)OH from hydrolysis and reactivation.

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Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase

et al. 2011

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Reactivation of VX-inhibited AChE by novel oximes having two oxygen atoms in the linker

Cited by 7 publications

References 27 publications

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase

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