Pseudomonas aeruginosa Lectin LecB as a Target in the Anti-Virulence Therapy : Towards Carbohydrate-based Anti-Adhesion Drugs

Content Provider	Semantic Scholar
Author	Sommer, Roman
Copyright Year	2016
Abstract	Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides L-fucose and D-mannose and conjugates thereof. Previously, D-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because D-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended D-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-D-mannoside. 102 All so far reported fucose-based inhibitors of LecB bear unmodified terminal α-L-fucosyl residues, an epitope which is recognized by numerous lectins of the host immune system, e.g. the selectins, DC-SIGN, MBL and others. In order to potentially increase target specificity and reduce interference with host lectins, high affinity mannose-based LecB inhibitors 2 and 3 with a camouflaged mannosyl residue through capping at C6 were recently reported. Figure 37: The LecB ligand methyl α-D-mannoside (1) forms a hydrogen bond through its 6-hydroxy group with Ser23. Mannose derivatives 2 and 3 are high affinity inhibitors of LecB, although unable to establish a hydrogen bond with Ser23. Mannoheptose derivatives 4 and 5 were designed to allow possible hydrogen bond formation of their 6-hydroxy group with Ser23 and attachment of additional pharmacophores (R). In contrast to its low affinity for this lectin, D-mannose forms an additional hydrogen bond in the crystal structure of its O6 with LecB at residue Ser23. Interestingly, this hydrogen bond does not contribute significantly to the overall binding affinity at ambient conditions (section 3.2.1). This observation could result from a high degree of flexibility of 1 in the unbound state, and thus increased entropy costs upon binding, a concept well established for the C-type lectin E-selectin and its carbohydrate ligand sialyl Lewis. Extension of mannose-derived ligand 1 with additional pharmacophores at C6 allows the targeting of adjacent protein surface and potent inhibitors, e.g. 2 and 3, were obtained. Although these compounds are LecB inhibitors with more than 20-fold improved affinity, the hydrogen bond with Ser23 cannot be established due the lack of O6. Additionally exploiting the interaction of Man-O6 by increasing O
File Format	PDF HTM / HTML
Alternate Webpage(s)	https://kops.uni-konstanz.de/bitstream/handle/123456789/34228/Sommer_0-341131.pdf?isAllowed=y&sequence=3
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article