2. Academic Validation
  3. Calcium Competitive Inhibition of Langerin by Thiazolopyrimidinones

Calcium Competitive Inhibition of Langerin by Thiazolopyrimidinones

  • J Med Chem. 2025 Dec 11;68(23):24924-24934. doi: 10.1021/acs.jmedchem.5c01756.
Yunzhan Ning 1 2,  Nina-Louisa Efrém 3,  Machoud Amoussa 3,  Ertan Turhan 4 5,  Dazhong Zheng 6 7,  Jonathan Lefèbre 1 2,  Max Ruwolt 8,  Ursula Neu 8,  Maurice Besch 1 2,  Bernhard Loll 8,  Dennis Kurzbach 4 5,  Jesko Köhnke 6 7,  Marc Nazaré 3,  Christoph Rademacher 1 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna 1090, Austria.
  • 2 Vienna Doctoral School of Pharmaceutical, Nutritional and Sport Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna 1090, Austria.
  • 3 Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, Berlin 13125, Germany.
  • 4 Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria.
  • 5 University of Vienna, Währinger Straße 38, Vienna 1090, Austria.
  • 6 Institute of Food Chemistry, Leibniz University Hannover, Callinstraße 5, Hannover 30167, Germany.
  • 7 School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom.
  • 8 Institute of Chemistry and Biochemistry, Laboratory of Structural Biochemistry, Freie Universität Berlin, Takustr. 6, Berlin 14195, Germany.
  • 9 Max Perutz Laboratories, Vienna Biocenter Campus (VBC), Dr.-Bohr-Gasse 9, Vienna 1030, Austria.
PMID: 41261040 DOI: 10.1021/acs.jmedchem.5c01756
Abstract

C-Type lectins are a large family of carbohydrate-binding proteins. Langerin is a member of this family and is expressed by Langerhans cells, involved in pathogen recognition and innate immune activation, making it a target for small-molecule modulation in immunology and infectious diseases. We previously identified thiazolopyrimidinones as a series of allosteric inhibitors, but the underlying mechanism remained unclear. In this study, 43CA NMR demonstrated that these fragments induce CA2+ release from the receptor. Our ITC data suggested a competitive relationship between inhibitors and CA2+, which was further validated by 19F NMR spectroscopy showing inhibition of carbohydrate binding. Surprisingly, the fragment binding site was found to be located beneath the long loop, which supports the dynamic nature of the long loop being highly CA2+ dependent. Our findings provide insight into the novel CA2+-competitive inhibitory mechanism of murine langerin and are the first report on such an inhibitory mechanism for a C-type lectin.

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