title: Synthetic variants of mycolactone bind and activate Wiskott-Aldrich syndrome proteins.
abstract: 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.
authors.affiliation: Laboratoire de Chimie Organique et Bioorganique, Université de Haute-Alsace, ENSCMu , 3 Rue A. Werner, 68093 Mulhouse Cedex, France.
authors.forename: Anne-Caroline
authors.initials: AC
authors.lastname: Chany
authors.forename: Romain
authors.initials: R
authors.lastname: Veyron-Churlet
authors.forename: Cédric
authors.initials: C
authors.lastname: Tresse
authors.forename: Véronique
authors.initials: V
authors.lastname: Mayau
authors.forename: Virginie
authors.initials: V
authors.lastname: Casarotto
authors.forename: Fabien
authors.initials: F
authors.lastname: Le Chevalier
authors.forename: Laure
authors.initials: L
authors.lastname: Guenin-Macé
authors.forename: Caroline
authors.initials: C
authors.lastname: Demangel
authors.forename: Nicolas
authors.initials: N
authors.lastname: Blanchard
mesh_terms: D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D019911:Mycobacterium ulcerans / Q000737:chemistry; D011485:Protein Binding; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D018942:Macrolides; D051316:Wiskott-Aldrich Syndrome Protein; C117218:mycolactone