Accession Number : ADA512546


Title :   Generation and Evaluation of PEGylated Recombinant Human Acetylcholinesterase as an Optimal OP-Bioscavenger


Descriptive Note : Final rept. 5 Jul 2006-31 Dec 2008


Corporate Author : ISRAEL INST FOR BIOLOGICAL RESEARCH NESS ZIONA


Personal Author(s) : Cohen, Ofer ; Kronman, Chanoch ; Shafferman, Avigdor


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a512546.pdf


Report Date : 27 Apr 2009


Pagination or Media Count : 26


Abstract : We have shown in the past that recombinant human AChE (rHuAChE) can be converted into circulatory long-lived molecular forms by conjugation of polyethylene glycol (PEG) chains to lysine residues. In the present study, we determined the factors that govern circulatory residence of PEGylated AChE, and established the lysine mutant configurations that allow maximal circulatory longevity. We further demonstrated that PEGylated rHuAChEs are less immunogenic than non-modified enzyme. In addition, we incorporated favorable kinetic characteristics for OP-scavenging into the rHuAChE enzyme, utilizing genetic engineering methods. Thus, incorporation of the F338A mutation into circulatory long-lived PEG-hypolysine AChE resulted in an enzyme displaying reduced aging rates that could protect mice against repeated OP-compound exposures. Finally, we established a method for production of enzymatically active rHAChE at appreciable amounts and relatively low cost utilizing the Pichia pastoris yeast cell system. Taken together, these different lines of study pave the way for large-scale production of PEGylated recombinant human AChE derivatives displaying catalytic and pharmacokinetic properties optimized for effective in-vivo bioscavenging of OP-compounds.


Descriptors :   *ORGANOPHOSPHATES , *ACETYLCHOLINESTERASE , EXPOSURE(PHYSIOLOGY) , GLYCOLS , AGING(PHYSIOLOGY) , ISRAEL , PHARMACOKINETICS


Subject Categories : Biochemistry
      Pharmacology
      Chemical, Biological and Radiological Warfare


Distribution Statement : APPROVED FOR PUBLIC RELEASE