Targeting undruggable carbohydrate recognition sites through focused fragment library design

Author:

Shanina Elena,Kuhaudomlarp Sakonwan,Siebs EikeORCID,Fuchsberger Felix F.,Denis Maxime,da Silva Figueiredo Celestino Gomes Priscila,Clausen Mads H.ORCID,Seeberger Peter H.,Rognan DidierORCID,Titz AlexanderORCID,Imberty AnneORCID,Rademacher ChristophORCID

Abstract

AbstractCarbohydrate-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.

Publisher

Springer Science and Business Media LLC

Subject

Materials Chemistry,Biochemistry,Environmental Chemistry,General Chemistry

Reference69 articles.

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