Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.
Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Francine S
FS
Katz
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Stevan
S
Pecic
Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027 (USA).
Timothy H
TH
Tran
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Ilya
I
Trakht
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Laura
L
Schneider
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Zhengxiang
Z
Zhu
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Long
L
Ton-That
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Michal
M
Luzac
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Viktor
V
Zlatanic
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Shivani
S
Damera
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).|Genecology Research Centre, Inflammation and Healing Research Cluster, School of Science and Engineering, University of the Sunshine Coast, 90 Sippy Downs Drive, Sippy Downs, QLD 4556 (Australia).
Joanne
J
Macdonald
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).
Donald W
DW
Landry
Department of Biological Sciences, Columbia University, 1212 Amsterdam Avenue, New York, NY 10027 (USA).
Liang
L
Tong
Department of Medicine/Division of Experimental Therapeutics, Columbia University Medical Center, 630 W. 168th Street, New York, NY 10032 (USA).|Departments of Biomedical Engineering and Systems Biology, Columbia University, 630 W. 168th street, New York, NY 10032 (USA).
Milan N
MN
Stojanovic
D000110:Acetylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D015394:Molecular Structure; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D010636:Phenols; D000110:Acetylcholinesterase
drug discovery; high-throughput screening; medicinal chemistry; neurological agents; structure-activity relationships