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 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.
School of Life Sciences and Biodesign Institute, P.O. Box 874501, Arizona State University, Tempe, AZ 85287-4501, USA.
Brian C
BC
Geyer
Latha
L
Kannan
Pierre-Emmanuel
PE
Garnaud
Clarence A
CA
Broomfield
C Linn
CL
Cadieux
Irene
I
Cherni
Sean M
SM
Hodgins
Shane A
SA
Kasten
Karli
K
Kelley
Jacquelyn
J
Kilbourne
Zeke P
ZP
Oliver
Tamara C
TC
Otto
Ian
I
Puffenberger
Tony E
TE
Reeves
Neil
N
Robbins
Ryan R
RR
Woods
Hermona
H
Soreq
David E
DE
Lenz
Douglas M
DM
Cerasoli
Tsafrir S
TS
Mor
D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002619:Chemical Warfare Agents / Q000378:metabolism / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D006168:Guinea Pigs; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000633:toxicity*; D010575:Pesticides / Q000378:metabolism / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000378:metabolism; D015202:Protein Engineering; D014026:Nicotiana / Q000378:metabolism*
D002619:Chemical Warfare Agents; D018696:Neuroprotective Agents; D009943:Organophosphorus Compounds; D010575:Pesticides; D011092:Polyethylene Glycols; D002091:Butyrylcholinesterase