TLC analysis of twelve different salts of oxime HI-6 — Reactivator of nerve agent inhibited AChE

Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme–sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

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Reactivation of nerve agent inhibited human acetylcholinesterases by HI-6 and obidoxime

Biochemical Pharmacology ◽

10.1016/0006-2952(86)90116-4 ◽

1986 ◽

Vol 35 (9) ◽

pp. 1505-1510 ◽

Cited By ~ 72

Author(s):

Gertrud Puu ◽

Elisabet Artursson ◽

Göran Bucht

Keyword(s):

Nerve Agent ◽

Hi 6

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Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

Nanoscale ◽

10.1039/c5nr06658a ◽

2016 ◽

Vol 8 (18) ◽

pp. 9537-9547 ◽

Cited By ~ 23

Author(s):

Jun Yang ◽

Lixue Fan ◽

Feijian Wang ◽

Yuan Luo ◽

Xin Sui ◽

...

Keyword(s):

Mesoporous Silica ◽

Silica Nanoparticles ◽

Mesoporous Silica Nanoparticles ◽

Nerve Agent ◽

Hi 6 ◽

The Brain

Transferrin-modified mesoporous silica nanoparticles could rapidly deliver and release an antidote to the brain for effectively detoxifying nerve agent poisoning.

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Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6

Archives of Toxicology ◽

10.1007/s00204-016-1776-x ◽

2016 ◽

Vol 91 (3) ◽

pp. 1309-1318 ◽

Cited By ~ 6

Author(s):

Timo Wille ◽

Jens von der Wellen ◽

Horst Thiermann ◽

Franz Worek

Keyword(s):

Human Blood ◽

Nerve Agent ◽

Blood Components ◽

Hi 6

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A Comparison of the Therapeutic Efficacy of Conventional and Modern Oximes Against Supralethal Doses of Highly Toxic Organophosphates in Mice

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2019.162 ◽

1998 ◽

Vol 41 (1) ◽

pp. 19-21 ◽

Cited By ~ 4

Author(s):

Jiří Kassa

Keyword(s):

Therapeutic Efficacy ◽

Nerve Agent ◽

Hi 6 ◽

Hlö 7

1. The therapeutic efficacy of various oximes (pralidoxime, obidoxime, methoxime, HI-6, HLö-7, BI-6) against supralethal nerve agent poisoning (soman, sarin, cyclosin) in mice was tested. 2. New oxime BI-6, synthesized in our laboratory, is significantly more efficacious than conventional oximes but a little less efficacious than other H-oximes (HI- 6, HLö-7). 3. H-oximes (HI-6, HLö-7) seem to be the most efficacious reactivators of nerve agent-inhibited acetylcholinesterase for antidotal treatment of supralethal nerve agent poisoning in mice.

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