Chemical Biology of Carbohydrates

Prof. Dr. Alexander Titz

Saarland University

Abstract

LECTINS AND GLYCOMIMETICS IN INFECTIOUS DISEASES

Lectins are exploited for initial infection by numerous pathogens such as bacteria, viruses and parasites.[1] In this talk, I will present our work on the synthesis of glycomimetics for bacterial and viral lectins and their biological evaluation. Bacterial biofilms are a severe problem for therapy. The Gram-negative bacterium P. aeruginosa is a critical bacterial pathogen as defined by the WHO priority pathogen list. This bacterium is difficult to treat due to excessive development of resistance to antibiotics and its abundant biofilm formation. The latter is a major resistance determinant of this pathogen since the biofilm shields embedded bacteria from chemotherapy and host defence. Therefore, several approaches to identify new anti-infectives against this bacterium aim to block biofilm formation. P. aeruginosa utilises the two lectins LecA (PA-IL) and LecB (PA-IIL) for initial adhesion to the host, for biofilm formation and as virulence factors. These are promising drug targets that are addressed in our research for therapeutics, diagnostics and conjugates.[2-7] Various other ESKPAE pathogens have lectins that may serve as drug targets in the future.
Sialic acids are recognized by numerous viruses, especially those with pandemic potential such as influenza and coronaviruses. Our work on the generation of sialic acid mimetics and their implementation into glycan arrays for the analysis of viral lectin binding will be discussed.

References

[1]Leusmann, S.; Menova, P.; Shanin, E.; Titz, A., Rademacher, C. Glycomimetics, Chem. Soc. Rev. 2023, 52, 3663-3740.
[2]Zahorska, E.; Rosato, F.; Stober, K.; Kuhaudomlarp, S.; Meiers, J.; Hauck, D.; Reith, D.; Gillon, E.; Rox, K.; Imberty, A.; Römer, W., Titz, A. Neutralizing the impact of the virulence factor LecA from Pseudomonas aeruginosa on human cells with new glycomimetic inhibitors, Angew. Chem. Int. Ed. Engl. 2023, 62(7), e202215535.
[3]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, 60(15), 8104-8114.
[4]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.
[5]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.
[6] Leusmann, S.; Siebs, E.; Varrot, A.; Kuhaudomlarp, S.; Imberty, A:; Kuhn, B.; Lerner, C.; Grether, U.; Titz, A.* The Parkinson’s disease drug Tolcapone and derivatives are potent glycomimetic lectin inhibitors of Pseudomonas aeruginosa LecA, Angew. Chem. Int. Ed. Engl. 2025, in press doi.org/10.1002/anie.202508864
[7]Zahorska, E.; Denig, L. M.; Lienenklaus, S.; Kuhaudomlarp, S.; Tschernig, T.; Lipp, P.; Munder, A.; Gillon, E.; Minervini, S.; Verkhova, V.; Imberty, A:; Wagner, S.; Titz, A. High Affinity Lectin-ligands Enable Detection of Pathogenic Pseudomonas aeruginosa Biofilms – Implications for Diagnostics and Therapy, JACS Au, 2024, 4, 4715–4728, https://doi.org/10.1021/jacsau.4c00670

About Prof Dr Alexander Titz

Alexander Titz studied chemistry at the Technical University Darmstadt and the University of Bordeaux I. For his diploma thesis, he moved to the Protein Structure Unit at Novartis Pharma in Basel. After receiving his doctorate from the University of Basel in 2008, covering the medicinal chemistry of carbohydrate-protein interactions, he conducted post-doctoral research at the Institute of Microbiology and Immunology at ETH Zürich (Swiss Federal Institute of Technology). In 2010, he was awarded the Klaus-Grohe Prize for medicinal chemistry of the GDCh.

After establishing a research group at the Zukunftskolleg of the University of Constance focusing on carbohydrate chemistry and inhibitors of bacterial biofilm formation, Alexander Titz has been head of the research group ‘Chemical Biology of Carbohydrates’ at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), an outpost of the Helmholtz Centre for Infection Research, since 2013. His group is furthermore part of the German Centre for Infection Research (DZIF), a national association of the German Centres for Health Research. Alexander Titz is teaching at Saarland University since 2014 and has been appointed Juniorprofessor for Chemical Biology in 2018.
Since 2017, the research in the Titz lab is funded by an ERC starting grant of the European Research Council. In 2018, Alexander Titz was awarded the Innovation Award in Medical/Pharmaceutical Chemistry by the German Chemical Society and the German Pharmaceutical Society as well as the Prize for a Young Medicinal Chemist in Academia of the European Federation of Medicinal Chemistry (EFMC). In 2019, Alexander obtained a call for the professorship for Organic Chemistry at the University of Osnabrück. Since 2020, Alexander Titz holds a professorship for Organic and Pharmaceutical Chemistry at Saarland University.

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Invited Lecture – LECTINS AND GLYCOMIMETICS IN INFECTIOUS DISEASES