Alvarez Dorta Dimitri, Chalopin Thibaut, Sivignon Adeline, de Ruyck Jérôme, Dumych Tetiana I, Bilyy Rostyslav O, Deniaud David, Barnich Nicolas, Bouckaert Julie, Gouin Sébastien G
LUNAM Université, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322, Nantes Cedex 3, France.
Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, 63000, Clermont-Ferrand, France.
ChemMedChem. 2017 Jun 21;12(12):986-998. doi: 10.1002/cmdc.201700061. Epub 2017 Apr 10.
Thiazolylaminomannosides (TazMan) are FimH antagonists with anti-adhesive potential against adherent-invasive Escherichia coli (AIEC) promoting gut inflammation in patients with Crohn's disease. The lead TazMan is highly potent in vitro, but shows limited in vivo efficiency, probably due to low pH stability and water solubility. We recently developed a second generation of stable TazMan, but the anti-adhesive effect was lower than the first. Herein we report a co-crystal structure of the lead TazMan in FimH, revealing that the anomeric NH group and the second thiazole moiety provide a positive hydrogen bonding interaction with a trapped water molecule, and π-stacking with Tyr48 of FimH, respectively. Consequently, we developed NeoTazMan homologated with a methylene group for low-pH and mannosidase stability with a conserved NH group and bearing various heterocyclic aglycones. Microencapsulation of the lead NeoTazMan in γ-cyclodextrin dramatically improved water solubility without disrupting the affinity for FimH or the anti-adhesive effect against AIEC isolated from patients with Crohn's disease.
噻唑基氨基甘露糖苷（TazMan）是一种FimH拮抗剂，对粘附侵袭性大肠杆菌（AIEC）具有抗粘附潜力，AIEC可促进克罗恩病患者肠道炎症。先导化合物TazMan在体外具有高效性，但体内效率有限，这可能是由于其低pH稳定性和水溶性所致。我们最近开发了第二代稳定的TazMan，但抗粘附效果低于第一代。在此，我们报道了先导化合物TazMan与FimH的共晶体结构，揭示了异头氨基和第二个噻唑部分分别与一个被困水分子形成正向氢键相互作用，并与FimH的Tyr48形成π-堆积。因此，我们开发了NeoTazMan，其通过亚甲基进行了同源化修饰，以提高低pH和甘露糖苷酶稳定性，同时保留保守的氨基并带有各种杂环苷元。将先导化合物NeoTazMan微囊化于γ-环糊精中可显著提高其水溶性，且不会破坏其对FimH的亲和力或对从克罗恩病患者分离出的AIEC的抗粘附效果。
