Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic ace...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 47; pp. 20251 - 20256
Main Authors:	Geyer, Brian C., Kannan, Latha, Garnaud, Pierre-Emmanuel, Broomfield, Clarence A., Cadieux, C. Linn, Cherni, Irene, Hodgins, Sean M., Kasten, Shane A., Kelley, Karli, Kilbourne, Jacquelyn, Oliver, Zeke P., Otto, Tamara C., Puffenberger, Ian, Reeves, Tony E., Robbins, Neil, Woods, Ryan R., Soreq, Hermona, Lenz, David E., Cerasoli, Douglas M., Mor, Tsafrir S., Arntzen, Charles J.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 23-11-2010 National Acad Sciences
Subjects:	Acetylcholinesterase Animals Biological Sciences Butyrylcholinesterase - metabolism Butyrylcholinesterase - pharmacokinetics Butyrylcholinesterase - pharmacology Chemical Warfare Agents - metabolism Chemical Warfare Agents - toxicity Cholinesterase Chromatography, High Pressure Liquid Clinical trials Disease control Dosage Drug interactions Enzymes Flowers & plants Guinea Pigs Humans hydrolase Immunoblotting Kinetics Mice Morbidity Mortality nerve agents Nerves Neuroprotective Agents - metabolism Neuroprotective Agents - pharmacokinetics Neuroprotective Agents - pharmacology Nicotiana - metabolism organophosphorus acid anhydride Organophosphorus Compounds - metabolism Organophosphorus Compounds - toxicity Oximes Pain Pesticides Pesticides - metabolism Pesticides - toxicity Pharmacokinetics Phosphorus Plants Poisoning Polyethylene glycol Polyethylene Glycols - metabolism Prophylaxis Protein Engineering Proteins Rodents Toxicity
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Summary:	The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 Author contributions: B.C.G., D.E.L., D.M.C., and T.S.M. designed research; B.C.G., L.K., P.-E.G., C.L.C., I.C., S.M.H., S.A.K., K.K., J.K., Z.P.O., T.C.O., I.P., T.E.R., N.R., and R.R.W. performed research; B.C.G., L.K., C.A.B., H.S., D.E.L., D.M.C., and T.S.M. analyzed data; and B.C.G., L.K., H.S., D.E.L., D.M.C., and T.S.M. wrote the paper. 2Present address: University of Arizona College of Medicine, 550 East Van Buren Street, Phoenix, AZ 85004. 3Present address: Cancer and Cell Biology Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004. 1B.C.G. and L.K. contributed equally to this work. Edited* by Charles J. Arntzen, Arizona State University, Tempe, AZ, and approved October 6, 2010 (received for review June 23, 2010)
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1009021107