Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• -functionalized mannosides as high-affinity FimH ligands and performed an extensive study on photo-crosslinking of the best ligand (mannoside 3) with a series of model peptides and FimH. Notably, we have employed high-performance mass spectrometry to be able to detect radiation results with the highest possible

• . Consequently, α-D-mannopyranosides having an aromatic aglycon portion such as p-nitrophenyl α-D-mannopyranoside (1) and the squaric acid derivative 2 [19] (Figure 3) were identified as FimH ligands with relative high affinity (low μmolar range). Based on this knowledge, we proposed the three diazirine-labeled

• of FimH ligands using FlexX flexible docking and consensus scoring, both implemented in Sybyl 6.9, as described earlier [19]. Two published X-ray structures of FimH (PDB codes 1KLF and 1UWF) were considered. During docking, the receptor was held fixed whereas the ligand was allowed to change its

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• be gained by such waters ranges from 0 kJ/mol for highly mobile waters to 8 kJ/mol for ordered and firmly bound waters. In contrast, the thermodynamic fingerprint of FimH ligands is enthalpically driven because an optimized, stable H-bond network is formed, and as a result, overcompensates the

Are D-manno-configured Amadori products ligands of the bacterial lectin FimH?

• Tobias-Elias Gloe,
• Insa Stamer,
• Cornelia Hojnik,
• Tanja M. Wrodnigg and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2015, 11, 1096–1104, doi:10.3762/bjoc.11.123

• site of the type 1-fimbrial lectin FimH. Keywords: Amadori rearrangement; bacterial adhesion; C-mannosides; docking studies; FimH ligands; Introduction The Amadori rearrangement (AR) is the reaction in which aldohexoses react with suitable amines under acidic catalysis to 1-amino-1-deoxyketohexoses

• investigation of ligands for the bacterial lectin FimH [4] it has been our goal to investigate the Amadori rearrangement as a method to approach new FimH ligands. These are especially relevant in the context of an anti-adhesion therapy against bacterial infections [5][6]. As FimH-mediated adhesion to the

• Amadori products with their axially oriented anomeric hydroxy group can function as a new class of FimH ligands. In addition, we can assume that Amadori products are stable against cleavage by mannosidases, as we found earlier that D-gluco-configured Amadori products are no substrates for glucosidases

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

• Vijayanand Chandrasekaran,
• Katharina Kolbe,
• Femke Beiroth and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2013, 9, 223–233, doi:10.3762/bjoc.9.26

• differs from many other docked FimH ligands. Here, the higher affinity for the open-gate FimH can be explained by strong π–π stacking of the first aromatic ring of the azobenzene unit with the tyrosine gate. As both isomers of 2 interact equally well with FimH, they can’t be used to switch type 1 fimbriae

• introduced lately and shown to be of medical relevance as FimH antagonists [6]. Thus, our novel “sweet switches” [15] appear to be highly promising FimH ligands, with the additional feature of a photoswitchable moiety. The biomedicinal potential of azobenzene glycosides seems even higher when their

En route to photoaffinity labeling of the bacterial lectin FimH

• Thisbe K. Lindhorst,
• Michaela Märten,
• Andreas Fuchs and
• Stefan D. Knight

Beilstein J. Org. Chem. 2010, 6, 810–822, doi:10.3762/bjoc.6.91

• modeling to predict binding of the various FimH ligands was carried out using FlexX flexible docking and consensus scoring as implemented in Sybyl 6.8 as described earlier [20]. Docking was based on published X-ray structures of the FimH CRD. This CRD was held fixed during the minimization, whereas the

• sugar ligand was allowed to change its conformation freely under the influence of the force field. ELISA ELISAs to determine IC50-values of the various FimH ligands were carried out with E. coli bacteria of strain HB101pPKL4 and mannan-coated microtiter plates as described earlier [21][22]. Mass