Improvements in scavenger protection against organophosphorus agents by modification of cholinesterases.
The ability of stoichiometric scavengers, such as ChEs, to protect against a variety of OP agents has been demonstrated in several in vivo models. To improve the detoxification of OP agents by ChEs, several approaches have been recently used to increase the stoichiometry, stability, and in vivo effectiveness of ChEs as OP scavengers. For example, the in vitro stoichiometric neutralization of sarin by AChE was increased from 1:1 to 3200:1 by the addition of the oxime HI-6, while the in vivo stoichiometry was increased to 57:1 in mice by HI-6. The aging rate of soman-inhibited mouse AChE was reduced 12-fold in a mutant AChE (E202Q) which resulted in a two-fold increase in oxime-assisted detoxification of soman. To improve the duration of scavenger protection provided by ChEs, the mean residence times of five tissue-derived and two recombinant ChEs injected i.v. in mice were compared with their oligosaccharide profiles. The mean residence times of these ChEs were found to increase with molecular weight and with the levels of oligosaccharide sialylation. The stability of AChE in non-physiological environments was improved by immobilizing it in a polyurethane foam matrix that allowed AChE to retain enzymatic activity at high temperature (75 degrees C) where soluble enzyme denatured. These developments in scavenger technology have improved the in vivo protection provided by OP scavengers and extended their applicability to provide external decontamination of chemical agents and pesticides.
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
D M
DM
Maxwell
A
A
Saxena
R K
RK
Gordon
B P
BP
Doctor
D000818:Animals; D000931:Antidotes / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity; D002802:Cholinesterases / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008658:Inactivation, Metabolic; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D002802:Cholinesterases