Improvement of Aglycone π‐Stacking Yields Nanomolar to Sub‐nanomolar FimH Antagonists

Abstract

Antimicrobial resistance has become a serious concern for the treatment of urinary tract infections. In this context, an anti‐adhesive approach targeting FimH, a bacterial lectin enabling the attachment of E. coli to host cells, has attracted considerable interest. FimH can adopt a low/medium‐affinity state in the absence and a high‐affinity state in the presence of shear forces. Until recently, mostly the high‐affinity state has been investigated, despite the fact that a therapeutic antagonist should bind predominantly to the low‐affinity state. In this communication, we demonstrate that fluorination of biphenyl α‐d‐mannosides leads to compounds with perfect π–π stacking interactions with the tyrosine gate of FimH, yielding low nanomolar to sub‐nanomolar KD values for the low‐ and high‐affinity states, respectively. The face‐to‐face alignment of the perfluorinated biphenyl group of FimH ligands and Tyr48 was confirmed by crystal structures as well as 1H,15N‐HSQC NMR analysis. Finally, fluorination improves pharmacokinetic parameters predictive for oral availability.

Enhancing the enthalpic contribution of hydrogen bonds by solvent shielding

“…The binding event is a single-step mechanism that proceeds without any major conformational adjustment of the residues in the mannose binding site. 26,27 On the other hand, the domain associated full-length FimH construct (FimH FL ) has been shown to bind mannoside ligands by a more complex mechanism caused by conformational distortions of the protein due to the presence of the regulatory subunit. 22,23 In the absence of a ligand, the protein exists in an ensemble of conformational states that are characterized by a shallow, solvent-exposed binding site, a low affinity to carbohydrate ligands, and a high degree of flexibility (FimH FL-open , Fig.…”

“…The weak entropic penalty has been linked to the rigidification of the tyrosine gate, an ensemble of hydrophobic residues that control access to the mannose binding site and interact with the aglycones of ligands 1-4. 26,27 An improved p-pstacking and hydrophobic interaction between aglycone and tyrosine gate further accentuates their thermodynamic profile, as the electrostatic nature of the aglycones gives rise to progressively tighter, enthalpy-driven binding from 4 -3 -2 -1.…”

Glycans in drug discovery

“…4). 48 In addition, prodrugs with improved oral bioavailability were also obtained by phosphorylation of FimH antagonists 49…”

The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations

“…The last years have enjoyed large advances in the Glycoscience field [6][7][8][9][10][11], providing new tools and perspectives to expand the understanding on the structure-function relationship of the events mediated by sugar-lectin interactions. These developments have also led to important progress in the use of glycomimetics [12,13], sugar analogues devised to bind lectins, antibodies, or enzymes [14][15][16].…”