Galektine und Toxine
Multivalente Systeme, wie zum Beispiel Glykopolymerbürsten, Neo-Glykoproteine und Glykan-funktionalisierte Mikrogele werden dazu benutzt, um gezielt Galektine und/oder Toxine zu adressieren (Diagnostik, Imaging).
Galektine gehören zu einer Lektin-Untergruppe, die spezifisch Glykane mit β-glykosidisch verknüpfter Galaktose (z.B. N-Acetyllactosamin) erkennt. Galektine besitzen mindestens eine globulär gefaltete Kohlenhydrate-Bindedomäne (CRD). Die wichtigsten Vertreter sind Galektin‑1 (Gal‑1) und Galektin‑3 (Gal‑3). Prototyp Gal‑1 enthält zwei identische CRDs, wohingegen Gal‑3 mithilfe einer N-terminalen Domäne befähigt ist polyvalente Aggregate (bis zum Pentamer) zu formen. Sowohl Gal‑1 und Gal‑3 erfüllen wichtige Funktionen bei Zell-Zell- und Zell-Matrix-Interaktionen und beeinflussen daher die Zelladhäsion und -migration, sind aber ebenfalls bei Immunantworten und Inflammationsereignissen beteiligt.
Clostridium difficile ist ein Krankenhauskeim, welcher das sog. Enterotoxin A (TcdA) ausscheidet. TcdA lagert sich an im Darm befindliche Epithelzellen an, wird endozytiert und unterbindet eine intrazelluläre Signalkaskade, was zu Läsionen im Darmepithel (Diarrhoe) führt. Die Zellanlagerung wird durch eine Lektin-Glykan Interaktion vermittelt. Wässrige Mikrogele mit Glykan-Einschlüssen und Neo-Glykoproteine werden zur Untersuchung der Spezifität und Bindungsverhalten von TcdA verwendet.
Publikationen zu Toxinen und Galektinen:
Beer, M.V., Rech, C., Gasteier, P., Sauerzapfe, B., Salber, J., Ewald, A., Möller, M., Elling, L., Groll, J., 2013. The Next Step in Biomimetic Material Design: Poly-LacNAc-Mediated Reversible Exposure of Extra Cellular Matrix Components. Advanced Healthcare Materials 2, 306-311. https://doi.org/10.1002/adhm.201200080.
Böcker, S., Elling, L., 2017a. Binding characteristics of galectin-3 fusion proteins. Glycobiology 27, 457-468. https://doi.org/10.1093/glycob/cwx007.
Böcker, S., Elling, L., 2017b. Biotinylated N-Acetyllactosamine- and N,N-Diacetyllactosamine-Based Oligosaccharides as Novel Ligands for Human Galectin-3. BioEng. 4, 31. https://doi.org/10.3390/bioengineering4020031.
Böcker, S., Laaf, D., Elling, L., 2015. Galectin Binding to Neo-Glycoproteins: LacDiNAc Conjugated BSA as Ligand for Human Galectin-3. Biomolecules 5, 1671-1696. https://doi.org/10.3390/biom5031671.
Boesveld, S., Jans, A., Rommel, D., Bartneck, M., Moller, M., Elling, L., Trautwein, C., Strnad, P., Kuehne, A.J.C., 2019. Microgels Sopping Up Toxins-GM1a-Functionalized Microgels as Scavengers for Cholera Toxin. ACS Applied Materials & Interfaces 11, 25017-25023. https://doi.org/10.1021/acsami.9b06413.
Bojarova, P., Tavares, M.R., Laaf, D., Bumba, L., Petraskova, L., Konefal, R., Blahova, M., Pelantova, H., Elling, L., Etrych, T., Chytil, P., Kren, V., 2018. Biocompatible glyconanomaterials based on HPMA-copolymer for specific targeting of galectin-3. J Nanobiotechnology 16, 73. https://doi.org/10.1186/s12951-018-0399-1.
Bumba, L., Laaf, D., Spiwok, V., Elling, L., Křen, V., Bojarová, P., 2018. Poly-N-Acetyllactosamine Neo-Glycoproteins as Nanomolar Ligands of Human Galectin-3: Binding Kinetics and Modeling. Internat. J. Mol. Sci. 19, 372. https://doi.org/10.3390/ijms19020372.
Filipová, M., Bojarová, P., Rodrigues Tavares, M., Bumba, L., Elling, L., Chytil, P., Gunár, K., Křen, V., Etrych, T., Janoušková, O., 2020. Glycopolymers for Efficient Inhibition of Galectin-3: In Vitro Proof of Efficacy Using Suppression of T Lymphocyte Apoptosis and Tumor Cell Migration. Biomacromolecules 21, 3122-3133. https://doi.org/10.1021/acs.biomac.0c00515.
Fischöder, T., Laaf, D., Dey, C., Elling, L., 2017. Enzymatic Synthesis of N-Acetyllactosamine (LacNAc) Type 1 Oligomers and Characterization as Multivalent Galectin Ligands. Molecules 22, 1320. https://doi.org/10.3390/molecules22081320.
Freichel, T., Heine, V., Laaf, D., Mackintosh, E.E., Sarafova, S., Elling, L., Snyder, N.L., Hartmann, L., 2020. Sequence-Defined Heteromultivalent Precision Glycomacromolecules Bearing Sulfonated/Sulfated Nonglycosidic Moieties Preferentially Bind Galectin-3 and Delay Wound Healing of a Galectin-3 Positive Tumor Cell Line in an In Vitro Wound Scratch Assay. Macromol. Biosci. 20, 2000163. https://doi.org/10.1002/mabi.202000163.
Freichel, T., Laaf, D., Hoffmann, M., Konietzny, P.B., Heine, V., Wawrzinek, R., Rademacher, C., Snyder, N.L., Elling, L., Hartmann, L., 2019. Effects of linker and liposome anchoring on lactose-functionalized glycomacromolecules as multivalent ligands for binding galectin-3. RSC Advances 9, 23484-23497. https://doi.org/10.1039/C9RA05497A.
Heine, V., Boesveld, S., Pelantova, H., Kren, V., Trautwein, C., Strnad, P., Elling, L., 2019. Identifying Efficient Clostridium difficile Toxin A Binders with a Multivalent Neo-Glycoprotein Glycan Library. Bioconj. Chem. 30, 2373-2383. https://doi.org/10.1021/acs.bioconjchem.9b00486.
Heine, V., Dey, C., Bojarova, P., Kren, V., Elling, L., 2022. Methods of in vitro study of galectin-glycomaterial interaction. Biotechnol. Adv. 58, 107928. https://doi.org/10.1016/j.biotechadv.2022.107928.
Heine, V., Hovorková, M., Vlachová, M., Filipová, M., Bumba, L., Janoušková, O., Hubálek, M., Cvačka, J., Petrásková, L., Pelantová, H., Křen, V., Elling, L., Bojarová, P., 2021. Immunoprotective neo-glycoproteins: Chemoenzymatic synthesis of multivalent glycomimetics for inhibition of cancer-related galectin-3. Eur. J. Med. Chem. 220, 113500. https://doi.org/10.1016/j.ejmech.2021.113500.
Hoffmann, M., Hayes, M.R., Pietruszka, J., Elling, L., 2020. Synthesis of the Thomsen-Friedenreich-antigen (TF-antigen) and binding of Galectin-3 to TF-antigen presenting neo-glycoproteins. Glycoconjugate J. 37, 457-470. https://doi.org/10.1007/s10719-020-09926-y.
Jans, A., Rosencrantz, R.R., Mandić, A.D., Anwar, N., Boesveld, S., Trautwein, C., Moeller, M., Sellge, G., Elling, L., Kuehne, A.J.C., 2017. Glycan-Functionalized Microgels for Scavenging and Specific Binding of Lectins. Biomacromolecules 18, 1460-1465. https://doi.org/10.1021/acs.biomac.6b01754.
Kupper, C.E., Böcker, S., Hulong Liu, Adamzyk, C., Kamp, J.v.d., Recker, T., Lethaus, B., Jahnen-Dechent, W., Neuss, S., Müller-Newen, G., Elling, L., 2013. Fluorescent SNAP-Tag Galectin Fusion Proteins as Novel Tools in Glycobiology. Current Pharmaceutical Design 19, 5457-5467.
Laaf, D., Bojarova, P., Elling, L., Kren, V., 2019. Galectin-Carbohydrate Interactions in Biomedicine and Biotechnology. Trends Biotechnol. 37, 402-415. https://doi.org/10.1016/j.tibtech.2018.10.001.
Laaf, D., Bojarová, P., Mikulová, B., Pelantová, H., Křen, V., Elling, L., 2017a. Two-Step Enzymatic Synthesis of β-D-N-Acetylgalactosamine-(1→4)-D-N-acetylglucosamine (LacdiNAc) Chitooligomers for Deciphering Galectin Binding Behavior. Adv. Synth. Catal. 359, 2101-2108. https://doi.org/10.1002/adsc.201700331.
Laaf, D., Bojarová, P., Pelantová, H., Křen, V., Elling, L., 2017. Tailored Multivalent Neo-Glycoproteins: Synthesis, Evaluation, and Application of a Library of Galectin-3-Binding Glycan Ligands. Bioconj. Chem. 28, 2832-2840. https://doi.org/10.1021/acs.bioconjchem.7b00520.
Laaf, D., Steffens, H., Pelantová, H., Bojarová, P., Křen, V., Elling, L., 2017b. Chemo-Enzymatic Synthesis of Branched N-Acetyllactosamine Glycan Oligomers for Galectin-3 Inhibition. Adv. Synth. Catal. 359, 4015-4024. https://doi.org/10.1002/adsc.201700969.
Römer, C.E., Elling, L., 2011. Galectins: structures, binding properties and function in cell adhesion, in: Pignatello, R. (Ed.) Biomaterials - Physics and Chemistry. IntechWeb.ORG, Rijeka, Croatia, pp. 3-28.
Rosencrantz, R.R., Nguyen, V.H., Park, H., Schulte, C., Böker, A., Schnakenberg, U., Elling, L., 2016. Lectin binding studies on a glycopolymer brush flow-through biosensor by localized surface plasmon resonance. Anal. Bioanal. Chem. 408, 5633-5640. https://doi.org/10.1007/s00216-016-9667-9.
Sauerzapfe, B., Křenek, K., Schmiedel, J., Wakarchuk, W.W., Pelantová, H., Křen, V., Elling, L., 2009. Chemo-enzymatic synthesis of poly-N-acetyllactosamine (poly-LacNAc) structures and their characterization for CGL2-galectin-mediated binding of ECM glycoproteins to biomaterial surfaces. Glycoconjugate J. 26, 141–159.
Šimonová, A., Kupper, C.E., Böcker, S., Müller, A., Hofbauerová, K., Pelantová, H., Elling, L., Křen, V., Bojarová, P., 2014. Chemo-enzymatic synthesis of LacdiNAc dimers of varying length as novel galectin ligands. J. Mol. Catal. B: Enzymatic 101, 47-55. https://doi.org/10.1016/j.molcatb.2013.12.018.
Tavares, M.R., Blahova, M., Sedlakova, L., Elling, L., Pelantova, H., Konefal, R., Etrych, T., Kren, V., Bojarova, P., Chytil, P., 2020. High-Affinity N-(2-Hydroxypropyl)methacrylamide Copolymers with Tailored N-Acetyllactosamine Presentation Discriminate between Galectins. Biomacromolecules 21, 641-652. https://doi.org/10.1021/acs.biomac.9b01370.
Zhang, H., Laaf, D., Elling, L., Pieters, R.J., 2018. Thiodigalactoside-Bovine Serum Albumin Conjugates as High-Potency Inhibitors of Galectin-3: An Outstanding Example of Multivalent Presentation of Small Molecule Inhibitors. Bioconj. Chem. 29, 1266-1275. https://doi.org/10.1021/acs.bioconjchem.8b00047.