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dc.contributor.authorChristie, Michelle P
dc.contributor.authorSimerska, Pavla
dc.contributor.authorJen, Freda E-C
dc.contributor.authorHussein, Waleed M
dc.contributor.authorRawi, Mohamad FM
dc.contributor.authorHartley-Tassell, Lauren E
dc.contributor.authorDay, Christopher J
dc.contributor.authorJennings, Michael P
dc.contributor.authorToth, Istvan
dc.date.accessioned2019-01-18T12:32:33Z
dc.date.available2019-01-18T12:32:33Z
dc.date.issued2014
dc.identifier.issn1932-6203
dc.identifier.doi10.1371/journal.pone.0095024
dc.identifier.urihttp://hdl.handle.net/10072/67439
dc.description.abstractGlycosylation 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 a-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 37é. 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 3.1ױ0-8 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 卩. 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.format.extent1719393 bytes
dc.format.mimetypeapplication/pdf
dc.languageEnglish
dc.language.isoeng
dc.publisherPublic Library of Science
dc.publisher.placeUnited States
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrome95024-1
dc.relation.ispartofpagetoe95024-10
dc.relation.ispartofissue4
dc.relation.ispartofjournalPloS One
dc.relation.ispartofvolume9
dc.rights.retentionY
dc.subject.fieldofresearchClinical pharmacology and therapeutics
dc.subject.fieldofresearchcode321402
dc.titleA Drug Delivery Strategy: Binding Enkephalin to Asialoglycoprotein Receptor by Enzymatic Galactosylation
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.rights.copyright© 2014 Christie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
gro.hasfulltextFull Text
gro.griffith.authorJennings, Michael P.
gro.griffith.authorDay, Christopher J.
gro.griffith.authorJen, Freda E.
gro.griffith.authorSimerska Taylor, Pavla


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