Over
50 years ago, the toxicity of irreversible organophosphate
inhibitors targeting human acetylcholinesterase (hAChE) was observed
to be stereospecific. The therapeutic reversal of hAChE inhibition
by reactivators has also been shown to depend on the stereochemistry
of the inhibitor. To gain clarity on the mechanism of stereospecific
inhibition, the X-ray crystallographic structures of hAChE inhibited
by a racemic mixture of VX (P
R/S
) and
its enantiomers were obtained. Beyond identifying hAChE structural
features that lend themselves to stereospecific inhibition, structures
of the reactivator HI-6 bound to hAChE inhibited by VX enantiomers
of varying toxicity, or in its uninhibited state, were obtained. Comparison
of hAChE in these pre-reactivation and post-reactivation states along
with enzymatic data reveals the potential influence of unproductive
reactivator poses on the efficacy of these types of therapeutics.
The recognition of structural features related to hAChE’s stereospecificity
toward VX shed light on the molecular influences of toxicity and their
effect on reactivators. In addition to providing a better understanding
of the innate issues with current reactivators, an avenue for improvement
of reactivators is envisioned.
The
threat of a deliberate release of chemical nerve agents has
underscored the need to continually improve field effective treatments
for these types of poisonings. The oxime containing HLö-7 is
a potential second-generation therapeutic reactivator. A synthetic
process for HLö-7 is detailed with improvements to the DIBAL
reduction and ion exchange steps. HLö-7 was visualized for
the first time within the active site of human acetylcholinesterase
and its relative ex vivo potency confirmed against
various nerve agents using a phrenic nerve hemidiaphragm assay.
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