title: Chemical Polysialylation and In Vivo Tetramerization Improve Pharmacokinetic Characteristics of Recombinant Human Butyrylcholinesterase-Based Bioscavengers.
abstract: Organophosphate toxins (OPs) are the most toxic low-molecular compounds. The extremely potent toxicity of OPs is determined by their specificity toward the nerve system. Human butyrylcholinesterase (hBChE) is a natural bioscavenger against a broad spectrum of OPs, which makes it a promising candidate for the development of DNA-encoded bioscavengers. The high values of the protective index observed for recombinant hBChE (rhBChE) make it appropriate for therapy against OP poisoning, especially in the case of highly toxic warfare nerve agents. Nevertheless, large-scale application of biopharmaceuticals based on hBChE is restricted due to its high cost and extremely rapid elimination from the bloodstream. In the present study, we examine two approaches for long-acting rhBChE production: I) chemical polysialylation and II) in-vivo tetramerization. We demonstrate that both approaches significantly improve the pharmacokinetic characteristics of rhBChE (more than 5 and 10 times, respectively), which makes it possible to use rhBChE conjugated with polysialic acids (rhBChE-CAO) and tetrameric rhBChE (4rhBChE) in the treatment of OP poisonings.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: S S
authors.initials: SS
authors.lastname: Terekhov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia ; Kazan' Federal University, Kremlevskaya Str., 18, Kazan', Republic of Tatarstan, 420000, Russia.
authors.forename: I V
authors.initials: IV
authors.lastname: Smirnov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: O G
authors.initials: OG
authors.lastname: Shamborant
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: T V
authors.initials: TV
authors.lastname: Bobik
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: D G
authors.initials: DG
authors.lastname: Ilyushin
authors.affiliation: Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, Moscow Region, 142290, Russia.
authors.forename: A N
authors.initials: AN
authors.lastname: Murashev
authors.affiliation: Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, Moscow Region, 142290, Russia.
authors.forename: I A
authors.initials: IA
authors.lastname: Dyachenko
authors.affiliation: Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Prospekt Nauki, 6, Pushchino, Moscow Region, 142290, Russia.
authors.forename: V A
authors.initials: VA
authors.lastname: Palikov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: V D
authors.initials: VD
authors.lastname: Knorre
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia ; Kazan' Federal University, Kremlevskaya Str., 18, Kazan', Republic of Tatarstan, 420000, Russia ; Institute of Gene Biology of the Russian Academy of Sciences, Vavilova Str., 34/5, Moscow, 119334 , Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Belogurov
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Ponomarenko
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia.
authors.forename: E S
authors.initials: ES
authors.lastname: Kuzina
authors.affiliation: Pharmsynthez, Krasnogo Kursanta Str., 25zh, Saint Petersburg, 197110, Russia.
authors.forename: D D
authors.initials: DD
authors.lastname: Genkin
authors.affiliation: Kazan' Federal University, Kremlevskaya Str., 18, Kazan', Republic of Tatarstan, 420000, Russia.
authors.forename: P
authors.initials: P
authors.lastname: Masson
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, Moscow, 117997, Russia ; Kazan' Federal University, Kremlevskaya Str., 18, Kazan', Republic of Tatarstan, 420000, Russia ; Institute of Gene Biology of the Russian Academy of Sciences, Vavilova Str., 34/5, Moscow, 119334 , Russia.
authors.forename: A G
authors.initials: AG
authors.lastname: Gabibov
keywords: biodistribution; biopharmaceutical; bioscavenger; butyrylcholinesterase; in vivo tetramerization; pharmacokinetics; polysialylation