Journal Article

PUBDB-2024-05772

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dimeric Lectin Chimeras as Novel Candidates for Gb3-Mediated Transcytotic Drug Delivery through Cellular Barriers

Xu, M. (Corresponding author) ; Antonova, M. ; Salavei, P. ; Illek, K. ; Meléndez, A. V. ; Omidvar, R. ; Thuenauer, R.Extern*CSSB* ; Makshakova, O. ; Roemer, W. (Corresponding author)Extern*

2023
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/pharmaceutics15010225  doi:10.3204/PUBDB-2024-05772

Abstract: Receptor-mediated transcytosis is an elegant and promising strategy for drug delivery across biological barriers. Here, we describe a novel ligand–receptor pair based on a dimeric, engineered derivative of the Pseudomonas aeruginosa lectin LecA, here termed Di-LecA, and the host cell glycosphingolipid Gb3. We characterized the trafficking kinetics and transcytosis efficiencies in polarized Gb3-positive and -negative MDCK cells using mainly immunofluorescence in combination with confocal microscopy. To evaluate the delivery capacity of dimeric LecA chimeras, EGFP was chosen as a fluorescent model protein representing macromolecules, such as antibody fragments, and fused to either the N- or C-terminus of monomeric LecA using recombinant DNA technology. Both LecA/EGFP fusion proteins crossed cellular monolayers in vitro. Of note, the conjugate with EGFP at the N-terminus of LecA (EGFP-LecA) showed a higher release rate than the conjugate with EGFP at the C-terminus (LecA-EGFP). Based on molecular dynamics simulations and cross-linking studies of giant unilamellar vesicles, we speculate that EGFP-LecA tends to be a dimer while LecA-EGFP forms a tetramer. Overall, we confidently propose the dimeric LecA chimeras as transcytotic drug delivery tools through Gb3-positive cellular barriers for future in vivo tests.Keywords:Gb3-binding lectin; glycosphingolipid; transcytosis; drug carrier; protein engineering; protein structure; valency; accelerated molecular dynamics

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Contributing Institute(s):

1. CSSB-CF-ALFM (CSSB-CF-ALFM)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)
2. DFG project G:(GEPRIS)39236281 - EXC 294: BIOSS Zentrum für Biologische Signalstudien - von der Analyse zur Synthese (39236281) (39236281)
3. DFG project G:(GEPRIS)390939984 - EXC 2189: CIBSS - Centre for Integrative Biological Signalling Studies (390939984) (390939984)

Experiment(s):

1. No specific instrument

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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