Targeting undruggable carbohydrate recognition sites through focused fragment library design.

Autor: Shanina E; Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14424, Potsdam, Germany.; Freie Universität Berlin, Department of Chemistry and Biochemistry, Arnimallee 22, 14195, Berlin, Germany., Kuhaudomlarp S; University Grenoble Alpes, CNRS, CERMAV, Grenoble, France.; Department of Biochemistry, Faculty of Science, Mahidol University, 10400, Bangkok, Thailand.; Center for Excellence in Protein and Enzyme Technology, Faculty of Science, Mahidol University, 10400, Bangkok, Thailand., Siebs E; Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany.; Saarland University, Department of Chemistry, 66123, Saarbrücken, Germany.; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany., Fuchsberger FF; Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14424, Potsdam, Germany.; Freie Universität Berlin, Department of Chemistry and Biochemistry, Arnimallee 22, 14195, Berlin, Germany.; University of Vienna, Department of Pharmaceutical Sciences, Althanstrasse 14, 1090, Vienna, Austria.; University of Vienna, Department of Microbiology, Immunology and Genetics, Max F. Berutz Labs, Biocenter 5, 1030, Vienna, Austria., Denis M; University of Vienna, Department of Pharmaceutical Sciences, Althanstrasse 14, 1090, Vienna, Austria.; University of Vienna, Department of Microbiology, Immunology and Genetics, Max F. Berutz Labs, Biocenter 5, 1030, Vienna, Austria., da Silva Figueiredo Celestino Gomes P; Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS-Université de Strasbourg, 67400, Illkirch, France.; Department of Physics, College of Sciences and Mathematics, Auburn University, 36849, Auburn, AL, USA., Clausen MH; Technical University of Denmark, Center for Nanomedicine and Theranostics, Department of Chemistry, Kemitorvet 207, 2800, Kongens Lyngby, Denmark., Seeberger PH; Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14424, Potsdam, Germany.; Freie Universität Berlin, Department of Chemistry and Biochemistry, Arnimallee 22, 14195, Berlin, Germany., Rognan D; Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS-Université de Strasbourg, 67400, Illkirch, France., Titz A; Chemical Biology of Carbohydrates (CBCH), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, 66123, Saarbrücken, Germany.; Saarland University, Department of Chemistry, 66123, Saarbrücken, Germany.; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany., Imberty A; University Grenoble Alpes, CNRS, CERMAV, Grenoble, France., Rademacher C; Max Planck Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14424, Potsdam, Germany. christoph.rademacher@univie.ac.at.; Freie Universität Berlin, Department of Chemistry and Biochemistry, Arnimallee 22, 14195, Berlin, Germany. christoph.rademacher@univie.ac.at.; University of Vienna, Department of Pharmaceutical Sciences, Althanstrasse 14, 1090, Vienna, Austria. christoph.rademacher@univie.ac.at.; University of Vienna, Department of Microbiology, Immunology and Genetics, Max F. Berutz Labs, Biocenter 5, 1030, Vienna, Austria. christoph.rademacher@univie.ac.at.
Jazyk: angličtina
Zdroj: Communications chemistry [Commun Chem] 2022 May 20; Vol. 5 (1), pp. 64. Date of Electronic Publication: 2022 May 20.
DOI: 10.1038/s42004-022-00679-3
Abstrakt: Carbohydrate-protein interactions are key for cell-cell and host-pathogen recognition and thus, emerged as viable therapeutic targets. However, their hydrophilic nature poses major limitations to the conventional development of drug-like inhibitors. To address this shortcoming, four fragment libraries were screened to identify metal-binding pharmacophores (MBPs) as novel scaffolds for inhibition of Ca 2+ -dependent carbohydrate-protein interactions. Here, we show the effect of MBPs on the clinically relevant lectins DC-SIGN, Langerin, LecA and LecB. Detailed structural and biochemical investigations revealed the specificity of MBPs for different Ca 2+ -dependent lectins. Exploring the structure-activity relationships of several fragments uncovered the functional groups in the MBPs suitable for modification to further improve lectin binding and selectivity. Selected inhibitors bound efficiently to DC-SIGN-expressing cells. Altogether, the discovery of MBPs as a promising class of Ca 2+ -dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.
(© 2022. The Author(s).)
Databáze: MEDLINE
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