Branched α-d-mannopyranosides: a new class of potent FimH antagonists

Abstract

FimH is a type I fimbrial lectin located at the tip of type-1 pili of uropathogenic Escherichia coli guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small-molecule antagonists is considered as a promising new therapeutic alternative to treat infections caused by uropathogenic Escherichia coli (UPEC). Herein we report that our recently disclosed a-D-mannopyranosides bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties act as potent FimH antagonists in vitro, as determined by a competitive binding assay on isolated FimH lectin. Most of the assayed compounds display FimH antagonistic activity in the range of 58-1000 nM. Based on the promising results of the first series of compounds, we have designed and synthesized a new series of asymmetrically disubstituted glyceryl a-D-mannopyranosides with improved physicochemical properties. Molecular docking calculations were employed to predict compounds' binding poses leading to two possible binding modes; so-called in-and out-docking modes in the "tyrosine gate" (formed by Tyr48 and Tyr137) for one aromatic moiety, which is in accordance with previous findings, while the second aromatic moiety reaches the previously unexplored lipophilic region formed by Phe142 and Ile13. Furthermore, compounds were found to be non-cytotoxic on HepG2 cells in concentrations up to 10 mM pointing to their selective toxicity, which is one of the key features of potential therapeutics for the treatment of urinary tract infections.

Sites for Dynamic Protein-Carbohydrate Interactions of O- and C-Linked Mannosides on the E. coli FimH Adhesin

“…In one of the two FimH molecules of the asymmetric unit of a crystal structure of the lectin domain in complex with a C -linked naphtyl mannose analog (PDB entry 5abz) [ 38 ], at least two alternative aglycon conformers were observed: a first one was bound between the two tyrosines in the open gate, whereas a second one hovered over the hydrophobic ridge above Phe142 ( Figure 3 D and Figure 4 D). The same binding mode was found in docking experiments using bivalent mannosidic inhibitors, posing one arm in the open tyrosine gate and one arm above the hydrophobic ridge [ 39 ].…”

“…Binding of anti-adhesives at the clamp loop holding Ile13 where large shear-force induced conformational changes occur, with the interplay of aglycon stacking with either the Ile13 or the Tyr48 side chain, is a mechanism as yet little explored in drug discovery of FimH antagonists of E. coli adhesion [ 42 ]. These novel structural insights, namely that ortho -biphenyl substituents on mannose can sample a binding interface on the FimH adhesin, notably one that is directly involved in the regulation of FimH affinity of pathogenic E coli under shear force, opens new perspectives for non-antibiotic therapies and anti-adhesive design [ 39 , 40 , 43 ].…”

Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease

“…Another approach to unique biaryl systems, relied on a branched 1,3-diaminopropanol or glycerol linker terminated by two aryl moieties [90]. Molecular modeling predicted an open tyrosine gate was best able to accommodate these derivatives, having one aryl moiety residing within the tyrosine gate in an ‘in-docking’ fashion, and the other located outside the gate, interacting with Phe142 and Ile13.…”

Giant strain geared to transformable H-bonded network in compressed β-d-mannose

“…31 For these and other reasons D-mannose is an important active pharmaceutical ingredient (API) often described as a healing sugar. 32 The considerably different metabolism of D-mannose and D-glucose results from their different codes of H-donor and H-acceptor hydroxyl groups, 33 convertible conformation and intermolecular interactions 34 adjusting to various environments. 35 The structure of the b-anomer of D-mannose crystals, despite its diverse applications, 29,30 has remained unknown until now.…”