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Plant-derived human acetylcholinesterase-R provides protection from lethal organophosphate poisoning and its chronic aftermath

Tama Evron^,1, Brian C. Geyer^*,1, Irene Cherni^*, Mrinalini Muralidharan^*, Jacquelyn Kilbourne^*, Samuel P. Fletcher^*, Hermona Soreq^,2 and Tsafrir S. Mor^*,2

^* School of Life Sciences and The Biodesign Institute, Arizona State University, Tempe, Arizona, USA; and

The Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel

²Correspondence: T.S.M., School of Life Sciences and Biodesign Inst, P.O. Box 874501, Arizona State University, Tempe, AZ 85287-4501, USA. E-mail: tsafrir.mor{at}asu.edu; H.S., The Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. E-mail: soreq{at}cc.huji.ac.il

Therapeutically valuable proteins are often rare and/or unstable in their natural context, calling for production solutions in heterologous systems. A relevant example is that of the stress-induced, normally rare, and naturally unstable "read-through" human acetylcholinesterase variant, AChE-R. AChE-R shares its active site with the synaptic AChE-S variant, which is the target of poisonous organophosphate anticholinesterase insecticides such as the parathion metabolite paraoxon. Inherent AChE-R overproduction under organophosphate intoxication confers both short-term protection (as a bioscavenger) and long-term neuromuscular damages (as a regulator). Here we report the purification, characterization, and testing of human, endoplasmic reticulum-retained AChE-R_ER produced from plant-optimized cDNA in Nicotiana benthamiana plants. AChE-R_ER purified to homogeneity showed indistinguishable biochemical properties, with IC₅₀ = 10^–7 M for the organophosphate paraoxon, similar to mammalian cell culture-derived AChE. In vivo titration showed dose-dependent protection by intravenously injected AChE-R_ER of FVB/N male mice challenged with a lethal dose of paraoxon, with complete elimination of short-term clinical symptoms at near molar equivalence. By 10 days postexposure, AChE-R prophylaxis markedly limited postexposure increases in plasma murine AChE-R levels while minimizing the organophosphate-induced neuromuscular junction dismorphology. Our findings present plant-produced AChE-R_ER as a bimodal agent, conferring both short- and long-term protection from organophosphate intoxication.—Evron, T., Geyer, B. C., Cherni, I., Muralidharan, M., Kilbourne, J., Fletcher, S. P., Soreq, H., Mor, T. S. Plant-derived human acetylcholinesterase-R provides protection from lethal organophosphate poisoning and its chronic aftermath.

Key Words: paraoxon intoxication • neuromuscular junction • transgenic plants • long-term protection • bioscavenger

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