Does size matter? - Comparing pyranoses with septanoses as ligands of the bacterial lectin FimH

Abstract

The pharmacological modulation of disease-relevant carbohydrate-protein interactions represents an underexplored area of medicinal chemistry. One particular challenge in the design of glycomimetic compounds is the inherent instability of the glycosidic bond toward enzymatic cleavage. This problem has traditionally been approached by employing S-, N-, or C-glycosides with reduced susceptibility toward glycosidases. The application of ring-extended glycomimetics is an innovative approach to circumvent this issue. On the example of the bacterial adhesin FimH, it was explored how design principles from pyranose glycomimetics transfer to analogous septanose structures. A series of ring-extended FimH antagonists exhibiting the well-proven pharmacophore necessary for targeting the tyrosine-gate of FimH was synthesized. The resulting septanoses were evaluated for their affinity to the conformationally rigid isolated lectin domain of FimH (FimH_LD), as well as a structurally flexible full-length FimH (FimH_FL) construct. Some elements of potent mannoside-based FimH antagonists could be successfully transferred to septanose-based ligands, ultimately resulting in a 32-fold increase in binding affinity. Interestingly, the canonical ca. 100-fold loss of binding affinity between FimH_LD and FimH_FL is partly mitigated by the more flexible septanose antagonists, hinting at potentially differing interaction features of the flexible glycomimetics with intermediately populated states during the conformational transition of FimH_FL.

Keywords: Antiadhesive therapy; Bacterial lectin; Glycomimetics; Septanose; Urinary tract infections.

Figure 1.

Ligands synthesized and evaluated for binding to FimH; n-heptyl septanose (1) and n-heptyl mannoside (2) have been studied earlier.^[22] Sepantoside 3 and septanoses 4 – 9 were synthesized and evaluated in the current communication.

Figure 2.

A) Crystal structure of n-heptyl mannosides (2) in complex with FimH_LD (PDB 4XO8). B) Crystal structure of septanose 1 in complex with FimH_LD (PDB 5CGB). Best scored poses of 7a (C) and 6 (D) from shape-based ligand-alignment docking with POSIT. The biphenyl pseudoaglycones of 7a and 6 interact with the tyrosine gate residues of FimH, while polar interactions in the mannose binding site are preserved.

Figure 3.

Thermodynamic fingerprints of 6 and 8a–c interacting with FimH_LD. Numeric data is given in Table S3.

Scheme 1.

Synthesis of n-heptyl 2-deoxy septanoside 3.

Scheme 2.

Synthesis of protected C2-O-methyl biphenyl septanoses 7a-b and 9a-c.

Scheme 3.

Synthesis of C2-O- biphenyl septanose 6.

Scheme 4.

Synthesis of C2-O-biphenyl septanoses 8a–c.

Scheme 5.

Synthesis of C2-O- alkylated septanoses 1, 4, 5, and 7c.