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

Brian C. Geyer, Latha Kannan, Pierre Emmanuel Garnaud, Clarence A. Broomfield, C. Linn Cadieux, Irene Cherni, Sean M. Hodgins, Shane A. Kasten, Karli Kelley, Jacquelyn Kilbourne, Zeke P. Oliver, Tamara C. Otto, Ian Puffenberger, Tony E. Reeves, Neil Robbins, Ryan R. Woods, Hermona Soreq, David E. Lenz, Douglas M. Cerasoli, Tsafrir Leket-Mor

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)20251-20256
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number47
DOIs
StatePublished - Nov 23 2010

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Keywords

  • Countermeasures
  • Nonconventional warfare agents
  • Organophosphorous pesticides
  • Protein engineering
  • Transgenic plants

ASJC Scopus subject areas

  • General

Cite this

Geyer, B. C., Kannan, L., Garnaud, P. E., Broomfield, C. A., Cadieux, C. L., Cherni, I., Hodgins, S. M., Kasten, S. A., Kelley, K., Kilbourne, J., Oliver, Z. P., Otto, T. C., Puffenberger, I., Reeves, T. E., Robbins, N., Woods, R. R., Soreq, H., Lenz, D. E., Cerasoli, D. M., & Leket-Mor, T. (2010). Plant-derived human butyrylcholinesterase, but not an organophosphorous- compound hydrolyzing variant thereof, protects rodents against nerve agents. Proceedings of the National Academy of Sciences of the United States of America, 107(47), 20251-20256. https://doi.org/10.1073/pnas.1009021107