Glycobiology (Oxford), 2006-08, Vol.16 (8), p.757-765
2006
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- Autor(en) / Beteiligte
- Titel
- Design of new benzoxazole-2-thione-derived inhibitors of Streptococcus pneumoniae hyaluronan lyase: structure of a complex with a 2-phenylindole
- Ist Teil von
- Glycobiology (Oxford), 2006-08, Vol.16 (8), p.757-765
- Ort / Verlag
- England: Oxford University Press
- Erscheinungsjahr
- 2006
- Quelle
- Oxford Journals 2020 Medicine
- Beschreibungen/Notizen
- The bacterial hyaluronan lyases (Hyals) that degrade hyaluronan, an important component of the extracellular matrix, are involved in microbial spread. Inhibitors of these enzymes are essential in investigation of the role of hyaluronan and Hyal in bacterial infections and constitute a new class of antibiotics against Hyal-producing bacteria. Recently, we identified 1,3-diacetylbenzimidazole-2-thione and related molecules as inhibitors of streptococcal Hyal. One of such compounds, 1-decyl-2-(4-sulfamoyloxyphenyl)-1-indol-6-yl sulfamate, was co-crystallized in a complex with Streptococcus pneumoniae Hyal and its structure elucidated. The resultant X-ray structure demonstrates that this inhibitor fits in the enzymatic active site via interactions resembling the binding mode of the natural hyaluronan substrate. X-ray structural analysis also indicates binding interactions with the catalytic residues and those of a catalytically essential hydrophobic patch. An IC₅₀ value of 11 μM for Hyal from Streptococcus agalactiae (strain 4755) qualifies this phenylindole compound as one of the most potent Hyal inhibitors known to date. The structural data suggested a similar binding mode for N-(3-phenylpropionyl)-benzoxazole-2-thione. This new compound's inhibitory properties were confirmed resulting in discovery of yet another Hyal inhibitor (IC₅₀ of 15 μM). These benzoxazole-2-thiones constitute a new class of inhibitors of bacterial Hyals and are well suited for further optimization of their selectivity, potency, and pharmacokinetic properties.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0959-6658eISSN: 1460-2423DOI: 10.1093/glycob/cwj116Titel-ID: cdi_proquest_miscellaneous_20443075
- Format
- –
- Schlagworte
- antimicrobials, Benzoxazoles - chemistry, Binding Sites, bovine serum albumin, BSA, cetyltrimethyl ammonium bromide, concentration for 50% inhibition, Crystallography, X-Ray, CTAB, dimethyl sulfoxide, dithiothreitol, DMSO, Drug Design, DTT, ECM, Enzyme Inhibitors - chemistry, extracellular matrix, Hyal, hyaluronan, hyaluronan lyases, hyaluronidase, Hydrogen Bonding, Hydrogen-Ion Concentration, IC50, Inhibitory Concentration 50, l-ascorbic acid, l-ascorbic acid-6-hexadecanoate, Models, Molecular, molecular mechanism, Molecular Structure, PDB, pneumococci, Polysaccharide-Lyases - antagonists & inhibitors, Protein Binding, Protein Data Bank, Protein Structure, Secondary, Protein Structure, Tertiary, rms, root mean square, SagHyal, SpnHyal, spreading factor, Streptococcus agalactiae, Streptococcus agalactiae hyaluronan lyase, Streptococcus pneumoniae, Streptococcus pneumoniae - enzymology, Streptococcus pneumoniae hyaluronan lyase, Structure-Activity Relationship, Substrate Specificity, Thiones - chemistry, Vcpal, Water - chemistry, X-Ray Diffraction