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

Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20251-6. doi: 10.1073/pnas.1009021107. Epub 2010 Nov 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Butyrylcholinesterase / metabolism
  • Butyrylcholinesterase / pharmacokinetics
  • Butyrylcholinesterase / pharmacology*
  • Chemical Warfare Agents / metabolism
  • Chemical Warfare Agents / toxicity*
  • Chromatography, High Pressure Liquid
  • Guinea Pigs
  • Humans
  • Immunoblotting
  • Kinetics
  • Mice
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / pharmacology*
  • Nicotiana / metabolism*
  • Organophosphorus Compounds / metabolism
  • Organophosphorus Compounds / toxicity*
  • Pesticides / metabolism
  • Pesticides / toxicity*
  • Polyethylene Glycols / metabolism
  • Protein Engineering

Substances

  • Chemical Warfare Agents
  • Neuroprotective Agents
  • Organophosphorus Compounds
  • Pesticides
  • Polyethylene Glycols
  • Butyrylcholinesterase