title: Probing the activity of a non-oxime reactivator for acetylcholinesterase inhibited by organophosphorus nerve agents.
abstract: Currently fielded treatments for nerve agent intoxication include atropine, an acetylcholine receptor antagonist, and pralidoxime (2PAM), a small molecule reactivator of acetylcholinesterase (AChE). 2PAM reactivates nerve agent-inhibited AChE via direct nucleophilic attack by the oxime moiety on the phosphorus center of the bound nerve agent. Due to a permanently charged pyridinium motif, 2PAM is not thought to cross the blood brain barrier and therefore cannot act directly in the neuronal junctions of the brain. In this study, ADOC, a non-permanently charged, non-oxime molecule initially identified using pesticide-inhibited AChE, was characterized in vitro against nerve agent-inhibited recombinant human AChE. The inhibitory and reactivation potentials of ADOC were determined with native AChE and AChE inhibited with tabun, sarin, soman, cyclosarin, VX, or VR and then compared to those of 2PAM. Several structural analogs of ADOC were used to probe the reactivation mechanism of the molecule. Finally, guinea pigs were used to examine the protective efficacy of the compound after exposure to sarin. The results of both in vitro and in vivo testing will be useful in the design of future small molecule reactivators.
authors.affiliation: Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. Electronic address: christena.l.cadieux.ctr@mail.mil.
authors.forename: C Linn
authors.initials: CL
authors.lastname: Cadieux
authors.affiliation: Chemistry and Biochemistry Department, University of Delaware, Newark, DE 19716, USA.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Chemistry and Biochemistry Department, University of Delaware, Newark, DE 19716, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Koenig
authors.affiliation: Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Shih
authors.affiliation: Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA.
authors.forename: John
authors.initials: J
authors.lastname: McDonough
authors.affiliation: Chemistry and Biochemistry Department, University of Delaware, Newark, DE 19716, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koh
authors.affiliation: Research Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Cerasoli
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002801:Cholinesterase Reactivators / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D004912:Erythrocytes / Q000201:enzymology; D006168:Guinea Pigs; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D000067397:Nerve Agents / Q000737:chemistry / Q000378:metabolism* / Q000506:poisoning; D062025:Organophosphate Poisoning / Q000188:drug therapy; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism; D010091:Oximes / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D012524:Sarin / Q000737:chemistry / Q000378:metabolism; D012999:Soman / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000613818:4-amino-2-((diethylamino)methyl)phenol; D002801:Cholinesterase Reactivators; D000067397:Nerve Agents; D010755:Organophosphates; D010091:Oximes; D010636:Phenols; D011220:Pralidoxime Compounds; D011994:Recombinant Proteins; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; C028797:pralidoxime; C009374:tabun
keywords: Acetylcholinesterase; Guinea pig; Organophosphorus nerve agent; Oxime; Pralidoxime; Reactivator