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  Targeting undruggable carbohydrate recognition sites through focused fragment library design

Shanina, E., Kuhaudomlarp, S., Siebs, E., Fuchsberger, F. F., Denis, M., da Silva Figueiredo Celestino Gomes, P., et al. (2022). Targeting undruggable carbohydrate recognition sites through focused fragment library design. Communications Chemistry, 5: 64. doi:10.1038/s42004-022-00679-3.

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Genre: Journal Article

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 Creators:
Shanina, Elena1, Author              
Kuhaudomlarp, Sakonwan, Author
Siebs, Eike, Author
Fuchsberger, Felix F.1, Author              
Denis, Maxime, Author
da Silva Figueiredo Celestino Gomes, Priscila, Author
Clausen, Mads H., Author
Seeberger, Peter H.2, Author              
Rognan, Didier, Author
Titz, Alexander, Author
Imberty, Anne, Author
Rademacher, Christoph1, Author              
Affiliations:
1Christoph Rademacher, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863300              
2Peter H. Seeberger - Automated Systems, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society, ou_1863306              

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 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.

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Language(s): eng - English
 Dates: 2022-05-202022
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s42004-022-00679-3
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Title: Communications Chemistry
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 5 Sequence Number: 64 Start / End Page: - Identifier: ISSN: 2399-3669