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Eva Zahorska Francesca Rosato Kai Stober Sakonwan Kuhaudomlarp Joscha Meiers Dirk Hauck Dorina Reith Emilie Gillon Katharina Rox Anne Imberty Winfried Römer Alexander Titz 《Angewandte Chemie (International ed. in English)》2023,62(7):e202215535
Bacterial adhesion, biofilm formation and host cell invasion of the ESKAPE pathogen Pseudomonas aeruginosa require the tetravalent lectins LecA and LecB, which are therefore drug targets to fight these infections. Recently, we have reported highly potent divalent galactosides as specific LecA inhibitors. However, they suffered from very low solubility and an intrinsic chemical instability due to two acylhydrazone motifs, which precluded further biological evaluation. Here, we isosterically substituted the acylhydrazones and systematically varied linker identity and length between the two galactosides necessary for LecA binding. The optimized divalent LecA ligands showed improved stability and were up to 1000-fold more soluble. Importantly, these properties now enabled their biological characterization. The lead compound L2 potently inhibited LecA binding to lung epithelial cells, restored wound closure in a scratch assay and reduced the invasiveness of P. aeruginosa into host cells. 相似文献
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Elena Shanina Sakonwan Kuhaudomlarp Kanhaya Lal Peter H. Seeberger Anne Imberty Christoph Rademacher 《Angewandte Chemie (International ed. in English)》2022,61(1):e202109339
Carbohydrate-binding proteins (lectins) are auspicious targets in drug discovery to combat antimicrobial resistance; however, their non-carbohydrate drug-like inhibitors are still unavailable. Here, we present a druggable pocket in a β-propeller lectin BambL from Burkholderia ambifaria as a potential target for allosteric inhibitors. This site was identified employing 19F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure–activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol?1 HA?1 that affected the orthosteric site. This effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets. Future drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic-resistant pathogens. 相似文献
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Sakonwan Kuhaudomlarp Linda Cerofolini Sabrina Santarsia Emilie Gillon Silvia Fallarini Grazia Lombardi Maxime Denis Stefano Giuntini Carolina Valori Marco Fragai Anne Imberty Alessandro Dondoni Cristina Nativi 《Chemical science》2020,11(47):12662
Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen Burkholderia ambifaria. A new fucoside analogue, with high affinity with BambL, firstly synthetized and co-crystallized with the protein target, provided the insights for sugar determinants grafting onto ubiquitin. Three ubiquitin-based glycosides were thus assembled. Fuc-Ub, presented several copies of the fucoside analogue, with proper geometry for multivalent effect; Rha-A28C, displayed one thio-rhamnose, known for its ability to tuning the immunological response; finally, Fuc-Rha-A28C, included both multiple fucoside analogs and the rhamnose residue. Fuc-Ub and Fuc-Rha-A28C ligands proved high affinity for BambL and unprecedented immune modulatory properties towards macrophages activation.Metal free click reactions used to glycosylate ubiquitin and its mutant A28C afforded two protein scaffolds with high affinity for Burkholderia ambifaria lectin (BambL). 相似文献
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