Capacity of oximes to bind and reactivate nerve agent‐inhibited butyrylcholinesterase
Abstract
Butyrylcholinesterase (BuChE) has promise as a stoichiometric prophylactic to protect against organophosphorus (OP) nerve agent poisoning. With an appropriate oxime, BuChE could be rapidly reactivated, making it quasi‐catalytic and enhance its protective efficacy. We examined the capacity of oximes known to be effective with acetylcholinesterase (2‐PAM, HI‐6, MMB‐4, TMB‐4, HS‐6, DAM and MINA) at different concentrations (10 mM – 10 μM) to reactivate BuChE inhibited by the nerve agents GA, GB, GF or VX. Only HI‐6 and HS‐6 were able to reactivate OP‐inhibited BuChE (GB and GF only) at a rate sufficiently fast to afford improved in vivo protective efficacy over enzyme alone. Thermodynamic parameters for the interaction of 2‐PAM and HI‐6 with BuChE were determined by isothermal titration calorimetry. Both interactions were found to have similar ΔG values (~ −5 kcal/mole). The binding of HI‐6 was exclusively enthalpically‐driven, while that of 2‐PAM had favorable entropic and enthalphic components. The results suggest that the tested oximes are inadequate to reactivate BuChE rapidly enough to make it an efficient quasi‐catalytic scavenger in vivo.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2008
- Source ID
- 10.1096/fasebj.22.1_supplement.649.6
Entities
Organizations
- Defense Threat Reduction Agency