Linked Life Data

18523134

Source:http://linkedlifedata.com/resource/pubmed/id/18523134

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-8-22
pubmed:abstractText
The high reactivity of cholinesterases (ChEs) toward organophosphorus (OP) compounds has led to propose recombinant ChEs as bioscavengers of nerve agents. The bioscavenging potential of recombinant ChEs can be enhanced by conjugation of polyethylene glycol (PEG) moieties, to extend their circulatory residence. However, the ability of exogenously administered ChEs to confer long-term protection against repeated exposures to nerve agents is still limited due to the aging process, whereby organophosphate-ChE adducts undergo irreversible dealkylation, which precludes oxime-mediated reactivation of the enzyme. To generate an optimal acetylcholinesterase (AChE)-based OP bioscavenger, the F338A mutation, known to decelerate the rate of aging of AChE-OP conjugates, was incorporated into polyethylene glycol-conjugated (PEGylated) human AChE. The PEGylated F338A-AChE displayed unaltered rates of hydrolysis, inhibition, phosphylation, and reactivation and could effectively protect mice against exposure to soman (pinacolylmethyl phosphonofluoridate), sarin (O-isopropyl methylphosphonofluoridate), or O-ethyl-S-(2-isopropylaminoethyl) methylphosphonothioate (VX). Unlike PEGylated wild-type (WT)-AChE, the PEGylated F338A-AChE exhibits significantly reduced aging rates after soman inhibition and can be efficiently reactivated by the 1-[[[4(aminocarbonyl)-pyridinio]methoxy]methyl]-2(hydroxyimino)methyl]pyridinium dichloride (HI-6) oxime, both in vitro and in vivo. Accordingly, oxime administration to PEG-F338A-AChE-pretreated mice enabled them to withstand repeated soman exposure (5.4 and 4 LD(50)/dose), whereas same regime treatment of non-PEGylated F338A-AChE- or PEGylated WT-AChE-pretreated mice failed to protect against the second challenge, due to rapid clearance or irreversible aging of the latter enzymes. Thus, judicious incorporation of selected mutations into the AChE mold in conjunction with its chemical modification provides means to engineer an optimal ChE-based OP bioscavenger in terms of circulatory longevity, resistance to aging, and reduced doses required for protection, even against repeated exposures to nerve agents, such as soman.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
74
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
755-63
pubmed:meshHeading
pubmed-meshheading:18523134-Acetylcholinesterase, pubmed-meshheading:18523134-Alanine, pubmed-meshheading:18523134-Amino Acid Substitution, pubmed-meshheading:18523134-Animals, pubmed-meshheading:18523134-Binding Sites, pubmed-meshheading:18523134-Cell Line, pubmed-meshheading:18523134-Cholinesterase Inhibitors, pubmed-meshheading:18523134-Enzyme Activation, pubmed-meshheading:18523134-Humans, pubmed-meshheading:18523134-Hydrolysis, pubmed-meshheading:18523134-Kinetics, pubmed-meshheading:18523134-Male, pubmed-meshheading:18523134-Mice, pubmed-meshheading:18523134-Mice, Inbred ICR, pubmed-meshheading:18523134-Organophosphorus Compounds, pubmed-meshheading:18523134-Phenylalanine, pubmed-meshheading:18523134-Phosphorylation, pubmed-meshheading:18523134-Polyethylene Glycols, pubmed-meshheading:18523134-Soman, pubmed-meshheading:18523134-Survival Analysis, pubmed-meshheading:18523134-Time Factors
pubmed:year
2008
pubmed:articleTitle
Aging-resistant organophosphate bioscavenger based on polyethylene glycol-conjugated F338A human acetylcholinesterase.
pubmed:affiliation
Israel Institute for Biological Research, Ness-Ziona 74100, Israel.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S.