title: Chemical polysialylation of human recombinant butyrylcholinesterase delivers a long-acting bioscavenger for nerve agents in vivo.
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.
authors.affiliation: Institute of Bioorganic Chemistry Russian Academy of Sciences, 117997 Moscow, Russia.
authors.forename: Denis G
authors.initials: DG
authors.lastname: Ilyushin
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Smirnov
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Belogurov
authors.forename: Igor A
authors.initials: IA
authors.lastname: Dyachenko
authors.forename: Tatiana Iu
authors.initials: TIu
authors.lastname: Zharmukhamedova
authors.forename: Tatjana I
authors.initials: TI
authors.lastname: Novozhilova
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Bychikhin
authors.forename: Marina V
authors.initials: MV
authors.lastname: Serebryakova
authors.forename: Oleg N
authors.initials: ON
authors.lastname: Kharybin
authors.forename: Arkadii N
authors.initials: AN
authors.lastname: Murashev
authors.forename: Konstantin A
authors.initials: KA
authors.lastname: Anikienko
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Nikolaev
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ponomarenko
authors.forename: Dmitry D
authors.initials: DD
authors.lastname: Genkin
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
authors.forename: Patrick
authors.initials: P
authors.lastname: Masson
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Gabibov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002091:Butyrylcholinesterase / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics*; D016466:CHO Cells; D002619:Chemical Warfare Agents / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D009946:Organothiophosphorus Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics; D012794:Sialic Acids / Q000737:chemistry
chemical_list: D002619:Chemical Warfare Agents; D018696:Neuroprotective Agents; D009946:Organothiophosphorus Compounds; D011994:Recombinant Proteins; D012794:Sialic Acids; D002091:Butyrylcholinesterase; C451779:S-(N,N-diethylaminoethyl) isobutyl methylphosphothiolate