Chemical Biology of Carbohydrates

Kuhaudomlarp, S.; Siebs, E.; Shanina, E.; Topin, J.; Joachim, I.; da Silva Figueiredo Celestino Gomes, P.; Varrot, A.; Rognan, D.; Rademacher, C.; Imberty, A.*, Titz, A.* Non-Carbohydrate Glycomimetics as Inhibitors of Calcium(II)-binding Lectins. Angew. Chem. Int. Ed. Engl.2021, in press, DOI: 10.1002/anie.202013217.

Sommer, R.; Wagner, S.; Rox, K.; Varrot, A.; Hauck, D.; Wamhoff, E.-C.; Schreiber, J.; Ryckmans, T.; Brunner, T.; Rademacher, C.; Hartmann, R. W.; Brönstrup, M.; Imberty, A.; Titz, A.* Glycomimetic, orally bioavailable LecB inhibitors block biofilm formation of Pseudomonas aeruginosa. J. Am. Chem. Soc. 2018, 140(7), 2537-2545, doi: 10.1021/jacs.7b11133.

Wagner, S.; Hauck, D.; Hoffmann, M.; Sommer, R.; Joachim, I.; Müller, R.; Imberty, A.; Varrot, A.; Titz, A.* Covalent lectin inhibition and its application in bacterial biofilm imaging. Angew. Chem. Int. Ed. Engl. 2017, 56, 16559-16564.

Beshr, G.; Sikandar, A.; Jemiller, E.-M.; Klymiuk, N.; Hauck, D.; Wagner, S.; Wolf, E.; Koehnke, J.*; Titz, A.* Photorhabdus luminescens lectin A (PllA) - a new probe for detecting α-galactoside-terminating glycoconjugates. J. Biol. Chem. 2017, 292(48), 19935-19951.

Sommer, R.; Wagner, S.; Varrot, A.; Nycholat, C.; Khaledi, A.; Häussler, S.; Paulson, J.; Imberty, A.; Titz, A.* The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug design. Chem. Sci. 2016, 7, 4990-5001.

Hauck, D.; Joachim, I.; Frommeyer, B.+; Varrot, A.; Philipp, B.; Möller, H.M.; Imberty, A.; Exner, T.E.; Titz, A.* Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes ACS Chem. Biol. 2013, 8(8), 1775–1784.

Research articles

Müller, M.; Calvert, C.; Hottmann, I.; Kluj, R.M.; Teufel, T.; Balbuchta, K.; Engelbrecht, A.; Selim, K.A.; Xu, Q.; Borisova, M.; Titz, A.; Mayer, C. Exo-β-N-acetylmuramidase NamZ of Bacillus subtilis is the founding member of a family of exolytic peptidoglycan hexosaminidases, J. Biol. Chem. 2021 in press.

Kuhaudomlarp, S.; Siebs, E.; Shanina, E.; Topin, J.; Joachim, I.; da Silva Figueiredo Celestino Gomes, P.; Varrot, A.; Rognan, D.; Rademacher, C.; Imberty, A.*, Titz, A.* Non-Carbohydrate Glycomimetics as Inhibitors of Calcium(II)-binding Lectins. Angew. Chem. Int. Ed. Engl. 2021, in press, DOI: 10.1002/anie.202013217.

Meiers, J.; Zahorska, E.; Röhrig, T.; Hauck, D.; Wagner, S.; Titz, A.* Directing Drugs to Bugs: Antibiotic-Carbohydrate Conjugates targeting Biofilm-associated Lectins of Pseudomonas aeruginosa. J. Med. Chem. 2020, doi: 10.1021/acs.jmedchem.0c00856, in press.

Shanina, E. V.; Siebs, E.; Zhang, H.; Silva, D. V.; Joachim, I.; Titz, A.; Rademacher, C. Protein-observed 19F NMR of LecA from Pseudomonas aeruginosa. Glycobiology 2020, doi: 10.1093/glycob/cwaa057 , in press.

Zahorska, E.; Kuhaudomlarp, S.; Minervini, S.; Yousaf, S.; Lepsik, M.; Kinsinger, T.; Hirsch, A. K. H.; Imberty, A.; Titz, A.* A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate. Chem. Commun. 2020, 56, 8822. 

Siebert, D. C. B.; Sommer, R.; Pogorevc, D.; Hoffmann, M.; Wenzel, S. C.; Müller, R.; Titz, A.*; Chemical Synthesis of Tripeptide Thioesters for the Biotechnological Incorporation into the Myxobacterial Secondary Metabolite Argyrin via Mutasynthesis. Beilstein J. Org. Chem.2019, 15, 2922–2929. doi:10.3762/bjoc.15.286

Sommer, R.; Rox, K.; Wagner, S.; Hauck, D.; Henrikus, S. S.; Newsad, S.; Arnold, T.; Ryckmans, T.; Brönstrup, M.; Imberty, A.; Varrot, A.; Hartmann, R.W.; Titz, A.* Anti-Biofilm Agents against Pseudomonas aeruginosa: a Structure-Activity Relationship of C-Glycosidic LecB inhibitors. J. Med. Chem.2019, 62(20), 9201-9216.

Lepsik, M.; Sommer, R.; Kuhaudomlarp, S.; Lelimousin, M.; Paci, E.; Varrot, A.; Titz, A.; Imberty, A. Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study. Eur. J. Med. Chem. 2019, 177, 212-220.

Lepsik, M.; Sommer, R.; Kuhaudomlarp, S.; Lelimousin, M.; Paci, E.; Varrot, A.; Titz, A.; Imberty, A. Induction of Rare Conformation of Oligosaccharide by Binding to Calcium-dependent Bacterial Lectin: X-ray Crystallography and Modelling Study. bioarXiv 2019, 612689; doi: https://doi.org/10.1101/612689

Dingjan, T.; Gillon, E.; Imberty, I.; Pérez, S.; Titz, A.; Ramsland, P.A.; Yuriev, E.* Virtual screening against carbohydrate-binding proteins: evaluation and application to bacterial Burkholderia ambifaria lectin. J. Chem. Inf. Model.2018, in press, doi: 10.1021/acs.jcim.8b00185.

Hottmann, I.; Mayer, V. M. T.; Tomek, M. B.; Friedrich, V.; Calvert, M. B.; Titz, A.; Schäffer, C. Mayer, C. N-Acetylmuramic acid (MurNAc) Auxotrophy of the Oral Pathogen Tannerella forsythia: Characterization of a MurNAc Kinase and Analysis of its Role in Cell Wall Metabolism. Frontiers in Microbiology2018, 9:19. doi: 10.3389/fmicb.2018.00019.

Sommer, R.; Wagner, S.; Rox, K.; Varrot, A.; Hauck, D.; Wamhoff, E.-C.; Schreiber, J.; Ryckmans, T.; Brunner, T.; Rademacher, C.; Hartmann, R. W.; Brönstrup, M.; Imberty, A.; Titz, A.* Glycomimetic, orally bioavailable LecB inhibitors block biofilm formation of Pseudomonas aeruginosa. J. Am. Chem. Soc.2018, 140(7), 2537-2545, doi: 10.1021/jacs.7b11133.

Calvert, M.; Mayer, C.; Titz, A.* An Efficient synthesis of 1,6-anhydromuramic acid from N-acetyl glucosamine. BeilsteinJ Org Chem2017, 13, 2631-2636.

Sommer, R.; Makshakova, O. N.; Wohlschlager, T.; Hutin, S.; Marsh, M.; Titz, A., Künzler, M.; Varrot, A. X-ray structures of Tectonin 2 from Laccaria bicolor revealed specific binding sites for methylated glycans and a unique tetrameric assembly with unprecedented multivalency. Structure 2018, 26(3), 391-402, doi: 10.1016/j.str.2018.01.003

Wagner, S.; Hauck, D.; Hoffmann, M.; Sommer, R.; Joachim, I.; Müller, R.; Imberty, A.; Varrot, A.; Titz, A.* Covalent lectin inhibition and application in bacterial biofilm imaging. Angew. Chem. Int. Ed. Engl.2017, 56, 16559-16564. doi: 10.1002/ange.201709368

Beshr, G.; Sikandar, A.; Jemiller, E.-M.; Klymiuk, N.; Hauck, D.; Wagner, S.; Wolf, E.; Koehnke, J.*; Titz, A.* Photorhabdus luminescens lectin A (PllA) - a new probe for detecting α-galactoside-terminating glycoconjugates. J. Biol. Chem.2017, 292(48), 19935-19951. doi: 10.1074/jbc.M117.812792

Hu, Y.; Beshr, G.; Garvey, C. J.; Tabor, R. F.; Titz, A.; Wilkinson, B. L. Photoswitchable Janus Glycodendrimer Micelles as Multivalent Inhibitors of LecA and LecB from Pseudomonas aeruginosa. Colloids Surf. B Biointerfaces  2017, 159, 605-612.

Sommer, R.; Hauck, D.; Titz, A.* Efficient two step β-glycoside synthesis from N-acetyl D-glucosamine: scope and limitations of copper(II) triflate-catalyzed glycosylation. ChemistrySelect2017, 2, 4187-4192.

Torge, A.; Wagner, S.; Chaves, P.S.; Oliveira, E.G.; Guterres, S.S.; Pohlmann, A.R.; Titz, A.; Schneider, M.; Beck, R.C.R. Ciprofloxacin-loaded lipid-core nanocapsules as mucus penetrating drug delivery system intended for the treatment of bacterial infections in Cystic Fibrosis. Int. J. Pharm.,2017, 527(1–2), 92-102.

Joachim, I.; Rikker, S.; Hauck, D.; Ponader, D.; Boden, S.; Sommer, R.; Hartmann, L.; Titz, A.* Development and optimization of a competitive binding assay for the galactophilic low affinity lectin LecA from Pseudomonas aeruginosa. Org. Biomol. Chem.2016, 14, 7933-7948.

Sommer, R.; Hauck, D.; Varrot, A.; Imberty, A.; Künzler, M.; Titz, A.* O-alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-l-selenofucoside. Beilstein J. Org. Chem.,2016, 12, 2828-2833.

Sommer, R.+; Wagner, S.+; Varrot, A.; Nycholat, C.; Khaledi, A.; Häussler, S.; Paulson, J.; Imberty, A.; Titz, A.* The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug design. Chem. Sci.2016, 7, 4990-5001.

Beshr, G.+; Sommer, R.+; Hauck, D.; Siebert, D.C.B.; Hofmann, A.; Imberty, A.; Titz, A.* Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors. Med. Chem. Commun.2016, 7, 519-530.

Sommer, R.; Hauck, D.; Varrot, A.; Wagner, S.; Prestel, A.; Möller, H.M.; Imberty, A.; Titz, A.* Cinnamide derivatives of D-mannose as inhibitors of the bacterial virulence factor LecB from Pseudomonas aeruginosa. ChemistryOpen2015, 4(6), 756-767.

Yan, S.; Brecker, L.; Jin, C.; Titz, A.; Dragosits, M.; Karlsson, N.; Jantsch, V.; Wilson, I.B.H.; Paschinger, K. Bisecting galactose as a feature of N-glycans in wild-type and mutant Caenorhabditis elegans. Mol Cell Proteomics2015, 14, 2111-2125.

Hofmann, A.+; Sommer, R.+; Hauck, D.; Stifel, J.; Göttker-Schnetmann, I.; Titz, A.* Synthesis of Mannoheptose Derivatives and their Evaluation as Inhibitors of the Lectin LecB from the Opportunistic Pathogen Pseudomonas aeruginosa. Carbohydr. Res.2015, 412, 34-42.

Wohlschlager, T.; Butschi, A.; Grassi, P.; Sutov, G.; Gauss, R.; Hauck, D.; Schmieder, S.; Knobel, M.; Titz, A.; Dell, A.; Haslam, S.M.; Hengartner, M.O.; Aebi, M.; Künzler, M. Methylated glycans as conserved targets of animal and fungal innate defense against bacteria and nematodes. Proc. Natl. Acad. Sci. USA2014, 111:E2787–E2796.

Mosca,S.; Keller, J.; Azzouz, N.; Wagner, S.; Titz, A.; Seeberger, P.H.; Brezesinski, G.; Hartmann, L. Amphiphilic cationic β3R3-peptides: membrane active peptidomimetics and their potential as antimicrobial agents. Biomacromolecules 2014, 15 (5), 1687–1695.

Sommer, R.; Exner, T.E.; Titz, A*. A Biophysical Study with Carbohydrate Derivatives Explains the Molecular Basis of Monosaccharide Selectivity of the Pseudomonas aeruginosa Lectin LecB PLoS ONE2014, 9(11): e112822.

Hauck, D.+; Joachim, I.+; Frommeyer, B.+; Varrot, A.; Philipp, B.; Möller, H.M.; Imberty, A.; Exner, T.E.; Titz, A.* Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes ACS Chem. Biol.2013, 8(8), 1775–1784.

Titz, A., Marra, A., Cutting, B., Smieško, M., Papandreou, G., Dondoni, A. and Ernst, B. Conformational Constraints: Nature Does It Best with Sialyl Lewisx. Eur. J. Org. Chem.2012, 5534–5539.

Butschi, A.+; Titz, A.+; Walti, M.+; Oleric, V.; Paschinger,, K.; Guo, X.; Nöbauer, K.; Seeberger, P.; Wilson, I.B.H.; Hengartner, M.O.; Aebi, M.; Künzler, M. Caenorhabditis elegans N-glycan core β-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2 PLoS Pathogens 2010, 6(1): e1000717. doi:10.1371/journal.ppat.1000717. + contributed equally

Titz, A.; Patton, J.; Smiesko, M.; Radic, Z.; Schwardt, O.; Magnani, J.L.; Ernst, B. Probing the Carbohydrate Recognition Domain of E-Selectin: The Importance of the Acid Orientation in sLex Mimetics Bioorg. Med. Chem.2010, 18(1), 19.

Titz, A.+; Butschi, A.+; Henrissat, B.; Fan, Y.-Y.; Hennet, T.; Razzazi-Fazeli, E.; Hengartner, M.O.; Wilson, I.B.H.; Künzler, M.; Aebi, M. Molecular basis for galactosylation of core fucose residues in invertebrates: Identification of Caenorhabditis elegans N-glycan core α-1,6 fucoside β-1,4-galactosyl-transferase GALT-1 as a member of a novel glycosyltransferase family J. Biol. Chem. 2009, 284(52), 36223. + contributed equally

Titz, A.; Patton, J.; Alker, A.; Porro, M.; Schwardt, O.; Hennig, M.; Francotte, E.; Magnani, J.; Ernst, B. Is adamantane a suitable substituent to pre-organize the acid orientation in E-selectin antagonists? Bioorg. Med. Chem.2008, 16, 1046.

Ramic, E.; Eichel, R.-A.; Dinse, K.-P.; Titz, A.; Schmidt, B. Complexation of copper(II)-chelidamate: multifrequency-pulsed electron paramagnetic resonance and electron nuclear double resonance analysis J. Phys. Chem. B 2006, 110, 20655 - 20663.

Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines Tetrahedron Lett. 2006, 47, 2383 - 2385.

Deffieux, D.; Fabre, I.; Titz, A.; Leger, J.-M.; Quideau, S. Electrochemical synthesis of dimerizing and nondimerizing orthoquinone monoketals J. Org. Chem.2004, 69, 8731 - 8738.

Schmidt, B.; Jiricek, J.; Titz, A.; Ye, G.; Parang, K. Copper dipicolinates as peptidomimetic ligands for the src SH2 domain Bioorg.Med. Chem. Lett.2004, 14(16), 4203-4206.

Reviews and book chapters

Hauck, D.; Jumde, V. R.; Crawford, C. J.; Titz, A.*; Optimized Henry reaction conditions for the synthesis of L-fucose C-glycosides. in Carbohydrate Chemistry: Proven Synthetic Methods 2021, Vol 5, chapter 3, page 17-23, CRC Press, Taylor & Francis, eds: P. Kosma, T. Wrodnigg, A. Stütz.

Wohlschlager, T.; Titz, A.; Künzler, M.; Varrot, A. Expression, purification and functional characterization of Tectonin 2 from Laccaria bicolor: a six-bladed beta-propeller lectin specific for O-methylated glycans. Lectin Purification and Analysis: Methods and Protocols, Hirabayashi, Jun (Ed.),  Methods in Molecular Biology, vol 2132, 669-682, Springer, 2020.

Meiers, J.; Siebs, E.; Zahorska, E.; Titz, A.* Lectin Antagonists in Infection, Inflammation and Immunity. Curr. Opin. Chem. Biol. 2019, 53, 51–67.

Calvert, M. B.; Jumde, V. R.;  Titz, A.* Pathoblockers or Anti-Virulence Drugs as a New Option for the Treatment of Bacterial Infections. Beilstein J. Org. Chem. 2018, 14, 2607–2617.

Wagner, S.+; Sommer, R.+; Hinsberger, S.; Lu, C.; Hartmann, R.W.; Empting, M.*; Titz, A.* Novel Strategies for the treatment of P. aeruginosa infections. J. Med. Chem.2016, 59 (13), 5929-5969.

Rodrigues, J.A.; Acosta-Serrano, A.; Aebi, M.; Ferguson, M.A.J.; Routier, F.H.; Schiller, I.; Soares, S.; Spencer, D.; Titz, A.; Wilson, I.B.H.; Izquierdo, L. Parasite glycobiology: A bittersweet symphony. PLoS Pathogens2015, 11(11): e1005169.

Titz, A*, Carbohydrate-Based Anti-Virulence Compounds Against Chronic Pseudomonas aeruginosa Infections with a Focus on Small Molecules Top. Med. Chem. Springer Berlin Heidelberg. 2014, 12, 169-186.

Sommer, R.; Joachim, I.; Wagner, S.; Titz, A*. New Approaches to Control Infections: Anti-Biofilm Strategies against Gram-Negative Bacteria. CHIMIA2013, 286-290.

Titz, A*. Biofilme Neue Forschungsansätze zur Therapie bakterieller Infektionskrankheiten GIT Labor-Fachzeitschrift2013, (2) 120-121.

Titz, A.; Ernst, B. Mimetics of Sialyl Lewisx: The Pre-Organization of the Carboxylic Acid is Essential for Binding to Selectins. CHIMIA 2007, 61, 194.

Patents

Zahorska, E.; Minervini, S.; Kuhaulumdorp, S.; Imberty, A.; Titz, A, Bivalent LecA inhibitors targeting Pseudomonas aeruginosa LecA. EP19306432.6.

Sommer, R.; Titz, A, Inhibitors of Pseudomonas aeruginosa LecB. WO2016/151066 A1. 

Titz, A. Glycomimetics as Pseudomonas aeruginosa lectin inhibitors. WO2013/152848 A1, granted patent.

Titz, A., Butschi, A., Aebi, M., Wilson, I.B.H., Hengartner, M., Künzler, M. Core beta-galactosyltransferase and uses thereof Patent. WO2010/136209 A1, granted patent.

Monograph

Titz, A. E-selectin and the Natural Tetrasaccharide Ligand sialyl Lewisx: The Importance of Pharmacophore Pre-Organization in Glyco-Mimetics, Dissertation, Universität Basel, 2008. Online available at http://edoc.unibas.ch/1054/