Targeting undruggable carbohydrate recognition sites through focused fragment library design
Issued Date
2022-12-01
Resource Type
eISSN
23993669
Scopus ID
2-s2.0-85130386422
Journal Title
Communications Chemistry
Volume
5
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Communications Chemistry Vol.5 No.1 (2022)
Suggested Citation
Shanina E., Kuhaudomlarp S., Siebs E., Fuchsberger F.F., Denis M., da Silva Figueiredo Celestino Gomes P., Clausen M.H., Seeberger P.H., Rognan D., Titz A., Imberty A., Rademacher C. Targeting undruggable carbohydrate recognition sites through focused fragment library design. Communications Chemistry Vol.5 No.1 (2022). doi:10.1038/s42004-022-00679-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/83544
Title
Targeting undruggable carbohydrate recognition sites through focused fragment library design
Author's Affiliation
Laboratoire d'Innovation Thérapeutique (LIT)
Université Grenoble Alpes
Universität des Saarlandes
Freie Universität Berlin
Universität Wien
Mahidol University
Helmholtz Centre for Infection Research (HZI)
Auburn University
Technical University of Denmark
Max-Planck-Institut für Kolloid- und Grenzflächenforschung
German Center for Infection Research (DZIF)
Université Grenoble Alpes
Universität des Saarlandes
Freie Universität Berlin
Universität Wien
Mahidol University
Helmholtz Centre for Infection Research (HZI)
Auburn University
Technical University of Denmark
Max-Planck-Institut für Kolloid- und Grenzflächenforschung
German Center for Infection Research (DZIF)
Other Contributor(s)
Abstract
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 Ca2+-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 Ca2+-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 Ca2+-dependent lectin inhibitors creates a foundation for fragment-based ligand design for future drug discovery campaigns.