A drug delivery strategy: binding enkephalin to asialoglycoprotein receptor by enzymatic galactosylation

Christie, Michelle P., Simerská, Pavla, Jen, Freda E.-C., Hussein, Waleed M., Rawi, Mohamad F. M., Hartley-Tassell, Lauren E., Day, Christopher J., Jennings, Michael P. and Toth, Istvan (2014) A drug delivery strategy: binding enkephalin to asialoglycoprotein receptor by enzymatic galactosylation. PLoS One, 9 4: e95024.1-e95024.10. doi:10.1371/journal.pone.0095024

Author Christie, Michelle P.
Simerská, Pavla
Jen, Freda E.-C.
Hussein, Waleed M.
Rawi, Mohamad F. M.
Hartley-Tassell, Lauren E.
Day, Christopher J.
Jennings, Michael P.
Toth, Istvan
Title A drug delivery strategy: binding enkephalin to asialoglycoprotein receptor by enzymatic galactosylation
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-04-15
Sub-type Article (original research)
DOI 10.1371/journal.pone.0095024
Open Access Status DOI
Volume 9
Issue 4
Start page e95024.1
End page e95024.10
Total pages 10
Editor Maria A. Deli
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2015
Language eng
Formatted abstract
Glycosylation of biopharmaceuticals can mediate cell specific delivery by targeting carbohydrate receptors. Additionally, glycosylation can improve the physico-chemical (drug-like) properties of peptide based drug candidates. The main purpose of this study was to examine if glycosylation of the peptide enkephalin could facilitate its binding to the carbohydrate receptor, asialoglycoprotein. Firstly, we described the one-pot enzymatic galactosylation of lactose modified enkephalin in the presence of uridine-5′-diphosphogalactose 4-epimerase and lipopolysaccharyl α-1,4-galactosyltransferase. Stability experiments using human plasma and Caco-2 cell homogenates showed that glycosylation considerably improved the stability of enkephalin (at least 60% remained stable after a 2 hr incubation at 37°C). In vitro permeability experiments using Caco-2 cells revealed that the permeability of mono- and trisaccharide conjugated enkephalins was 14 and 28 times higher, respectively, than that of enkephalin alone (Papp 3.1×10−8 cm/s). By the methods of surface plasmon resonance and molecular modeling, we demonstrated that the enzymatic glycosylation of enkephalin enabled binding the asialoglycoprotein receptor. The addition of a trisaccharide moiety to enkephalin improved the binding of enkephalin to the asialoglycoprotein receptor two fold (KD = 91 µM). The docking scores from molecular modeling showed that the binding modes and affinities of the glycosylated enkephalin derivatives to the asialoglycoprotein receptor complemented the results from the surface plasmon resonance experiments.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
School of Pharmacy Publications
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 05 May 2014, 15:14:45 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences