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Review
, 12 (7), 711-731

Rational Design Strategies for FimH Antagonists: New Drugs on the Horizon for Urinary Tract Infection and Crohn's Disease

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Review

Rational Design Strategies for FimH Antagonists: New Drugs on the Horizon for Urinary Tract Infection and Crohn's Disease

Laurel K Mydock-McGrane et al. Expert Opin Drug Discov.

Abstract

The bacterial adhesin FimH is a virulence factor and an attractive therapeutic target for urinary tract infection (UTI) and Crohn's Disease (CD). Located on type 1 pili of uropathogenic E. coli (UPEC), the FimH adhesin plays an integral role in the pathogenesis of UPEC. Recent efforts have culminated in the development of small-molecule mannoside FimH antagonists that target the mannose-binding lectin domain of FimH, inhibiting its function and preventing UPEC from binding mannosylated host cells in the bladder, thereby circumventing infection. Areas covered: The authors describe the structure-guided design of mannoside ligands, and review the structural biology of the FimH lectin domain. Additionally, they discuss the lead optimization of mannosides for therapeutic application in UTI and CD, and describe various assays used to measure mannoside potency in vitro and mouse models used to determine efficacy in vivo. Expert opinion: To date, mannoside optimization has led to a diverse set of small-molecule FimH antagonists with oral bioavailability. With clinical trials already initiated in CD and on the horizon for UTI, it is the authors, opinion that mannosides will be a 'first-in-class' treatment strategy for UTI and CD, and will pave the way for treatment of other Gram-negative bacterial infections.

Keywords: AIEC; Crohn’s disease; FimH; UPEC; UTI; bacterial adhesin; lectin; mannoside; pili; structure-based drug design (SBDD).

Figures

Figure 1
Figure 1
Molecular recognition of mannosylated receptors on the bladder surface by FimH adhesin of UPEC, residing on the outer tips of type 1 pili. Therapeutic rationale for FimH mannoside ligands in UTI and CD is to block adherence and invasion of bacteria.
Figure 2
Figure 2
FimH ligand binding affinity of A. early synthetic mannosides B. oligomannose-9 and subunits and C. other sugars.
Figure 3
Figure 3
Co-crystal structures of FimH and A. oligomannose-3, bound within an open tyrosine gate in an ‘in-docking’ mode (PDB code: 2VCO) and B. compound 6, bound in a closed tyrosine gate in an ‘outdocking’ mode (PDB code: 3MCY). The surface of the FimH receptor-binding site is subdivided into its hydrophobic support platform (grey; Phe142, Phe1 and Ile13), its polar pocket (red; Asn135, Asn138 and Asp140, and not shown Asn46, Asp47, Asp54, Gln133), the tyrosine gate (blue; Tyr137, Tyr48, and not shown Ile52) and Thr51 (cyan).
Figure 4
Figure 4
A. Schematic of residues in the polar mannose-binding pocket of the FimH lectin domain highlighting the extensive network of electrostatic and H-binding interactions of α-D-mannose with FimH. These interactions are responsible for the exquisite stereochemical specificity of FimH-containing bacteria for mannose. B. Binding pocket overlay of all reported FimH-mannoside X-ray structures showing the varied conformations of the tyrosine gate, with Tyr48 in grey (closed), blue (open) and green (open twisted), and the Tyr137 position invariant. Representative ligands shown are heptyl mannoside (yellow; 4LOV), 29 (green; 4X5Q), 18b (blue; 4AV0), and 25 (grey; 5F3F).
Figure 5
Figure 5
Overlay of 6 (yellow; 3MCY), 16 (green; 4CSS), 15 (blue; 5F2F) bound to the FimH lectin domain. Proximal ortho-pocket defined by residues Ile52, Asn138, Tyr137; Salt bridge defined by residues Arg98, Glu50; tyrosine gate defined by residues Tyr48, Tyr137, Thr51 (not shown). H-bonds to salt bridge and Tyr48 and Asp140 indicated with distances.
Figure 6
Figure 6
Structural diversity and activity of FimH mannoside antagonists.
Figure 7
Figure 7
Examples of medicinal chemistry modifications to the mannoside glycosidic bond.
Figure 8
Figure 8
Structures of mannoside prodrugs, multivalent, and disaccharide antagonists.

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