Abstract
The creation of effective bioscavengers as a pretreatment for exposure to nerve agents is a challenging medical objective. We report a recombinant method using chemical polysialylation to generate bioscavengers stable in the bloodstream. Development of a CHO-based expression system using genes encoding human butyrylcholinesterase and a proline-rich peptide under elongation factor promoter control resulted in self-assembling, active enzyme multimers. Polysialylation gives bioscavengers with enhanced pharmacokinetics which protect mice against 4.2 LD(50) of S-(2-(diethylamino)ethyl) O-isobutyl methanephosphonothioate without perturbation of long-term behavior.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Butyrylcholinesterase / administration & dosage
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Butyrylcholinesterase / chemistry*
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Butyrylcholinesterase / genetics
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Butyrylcholinesterase / pharmacokinetics*
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CHO Cells
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Chemical Warfare Agents / toxicity
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Cricetinae
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Cricetulus
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Humans
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Lethal Dose 50
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Male
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Mice
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Mice, Inbred BALB C
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Models, Molecular
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Molecular Sequence Data
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / chemistry*
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Neuroprotective Agents / pharmacokinetics*
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Organothiophosphorus Compounds / antagonists & inhibitors
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Organothiophosphorus Compounds / toxicity
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Recombinant Proteins / administration & dosage
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacokinetics
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Sialic Acids / chemistry
Substances
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Chemical Warfare Agents
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Neuroprotective Agents
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Organothiophosphorus Compounds
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Recombinant Proteins
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Sialic Acids
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Butyrylcholinesterase
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S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate