%0 Journal Article %T Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins %+ Laboratoire de Chimie organique et bioorganique (COB) %+ Immunobiologie de l'Infection %A Chany, Anne-Caroline %A Veyron-Churlet, Romain %A Tresse, Cédric %A Mayau, Véronique %A Casarotto, Virginie %A Le Chevalier, Fabien %A Guenin‐macé, Laure %A Demangel, Caroline %A Blanchard, Nicolas %Z This work received financial support from the “Association Raoul Follereau”, the “Fondation pour la Recherche Médicale, Equipes FRM 2012, Project DEQ20120323704”, the “Region Ile de France”, the CNRS, the University of Haute-Alsace, and the University of Strasbourg. %< avec comité de lecture %@ 0022-2623 %J Journal of Medicinal Chemistry %I American Chemical Society %V 57 %N 17 %P 7382 - 7395 %8 2014-09-02 %D 2014 %R 10.1021/jm5008819 %M 25158122 %Z Chemical SciencesJournal articles %X Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott−Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects. %G English %Z We thank Sandrine Vitry (Institut Pasteur, Paris, France) for helping us with the XCelligence assays of epithelial cell adhesion. %L pasteur-03320888 %U https://pasteur.hal.science/pasteur-03320888 %~ PASTEUR %~ CNRS %~ SITE-ALSACE %~ FRM %~ LABORATOIRES-UHA %~ UHA %~ CHERCHEURS-UHA-COTUTELLE %~ UHA-LIMA