Polyethylene glycosylation prolongs the circulatory stability of recombinant human butyrylcholinesterase

Chilukuri, Nageswararao; Parikh, Kalpana; Sun, Wei; Naik, Ramachandra S.; Tipparaju, Prasanthi; Doctor, Bhupendra P.; Saxena, Ashima

doi:10.1016/j.cbi.2005.10.013

Cited by 47 publications

(30 citation statements)

References 16 publications

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“…In principle, this methodology may serve for determination of PEG sites of other globular proteins of interest and especially that of BChE another ChE under development as an organophosphate bioscavenger. Like rAChE, rBChEs are also short-lived molecules in the circulation, unless they are modified posttranslationally or by PEGylation (13,27). In the case of rBChE, however, generation of homogenous PEGylated molecules would require some careful considerations.…”

Section: Discussionmentioning

confidence: 99%

Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants

Cohen

Kronman

Lazar

et al. 2007

Journal of Biological Chemistry

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Cholinesterases are efficient scavengers of organophosphates and are currently being developed as drugs for treatment against poisoning by such compounds. Recombinant ChE bioscavengers have very short circular longevity, a limitation that can be overcome by complex post-translation manipulations or by chemical modification such as polyethylene glycol conjugation. Series of multiple Lys-Ala mutants of human acetylcholinesterase were prepared allowing the generation of homogenous and well defined polyethylene-glycol conjugated AChEs with either one, two, three, four, or five appended polyethylene glycol (PEG) moieties/molecule. The rank order of circulatory longevity of these molecules was dependent on the number of PEG appendages up to a certain threshold: 5 ‫؍‬ 4 > 3 > 2 > 1 > 0. Hypolysine acetylcholinesterases (AChEs) carrying the same number of PEGs, and therefore with identical masses, allowed us to demonstrate that circulatory longevity correlates with the predicted extent of concealment of the AChE surface. Furthermore, circulatory profiles of high number and low number PEG-AChEs differing in their sialic acid contents demonstrate a direct relationship between PEG loading and the effective seclusion of AChE from the hepatic asialoglycoprotein receptor clearance system. Finally, an inverse relationship is found between the extent of PEG loading and the ability of the human acetylcholinesterase to elicit specific anti-HuAChE antibodies. In conclusion, these findings suggest that for the extension of circulatory longevity, protein surface domain concealment exerted by polyethylene glycol attachment is at least as important as its effect on size enlargement and highlights the role of PEG attachment in masking interactions between biomolecules and their cognate receptors.

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Section: Discussionmentioning

confidence: 99%

Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants

Cohen

Kronman

Lazar

et al. 2007

Journal of Biological Chemistry

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“…Production of recombinant adenoviruses expressing full-length Hu BChE (Ad-Hu BChE) and truncated Hu BChE (Ad-tHu BChE) was described previously (Chilukuri et al, 2005(Chilukuri et al, , 2008b.…”

Section: Methodsmentioning

confidence: 99%

“…Ad-expressed full-length and truncated rHu BChE from mouse plasma was partially purified by affinity chromatography using procainamide-Sepharose 4B gel (Chilukuri et al, 2005(Chilukuri et al, , 2008b. This was necessary because mouse plasma contains carboxylesterase, which competes with rHu BChE for binding to OPs.…”

mentioning

confidence: 99%

Adenovirus-Transduced Human Butyrylcholinesterase in Mouse Blood Functions as a Bioscavenger of Chemical Warfare Nerve Agents

et al. 2009

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“…31 However, the production of native human BuChE requires large amounts of plasma leading to the development of technologies to produce recombinant human BuChE. 32 Despite the fact that both AChE and BuChE serve as diagnostic tools, after the exposure resulting in inhibition levels <20% with no clinical signs and symptoms of organophosphate poisoning, it is necessary to bear in mind the uncertainty due to marked inter-individual variations of AChE and BuChE activities and to intra-individual variation of BuChE activities. 16,33 Another factor complicating the interpretation of erythrocyte AChE activity is that inhibition of this enzyme probably overestimates the inhibition of AChE in the nervous system.…”

Section: Mechanism Of Action Of Opcsmentioning

confidence: 99%

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

Antonijević¹,

Stojiljković²

2007

Clinical Medicine & Research

215

159

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Polyethylene glycosylation prolongs the circulatory stability of recombinant human butyrylcholinesterase

Cited by 47 publications

References 16 publications

Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants

Controlled Concealment of Exposed Clearance and Immunogenic Domains by Site-specific Polyethylene Glycol Attachment to Acetylcholinesterase Hypolysine Mutants

Adenovirus-Transduced Human Butyrylcholinesterase in Mouse Blood Functions as a Bioscavenger of Chemical Warfare Nerve Agents

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

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