Synthetic Variants of Mycolactone Bind and Activate Wiskott鈥揂ldrich Syndrome Proteins
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- 作者：Anne-Caroline Chany ; Romain Veyron-Churlet ; C茅dric Tresse ; V茅ronique Mayau ; Virginie Casarotto ; Fabien Le Chevalier ; Laure Guenin-Mac茅 ; Caroline Demangel ; Nicolas Blanchard
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：September 11, 2014
- 年：2014
- 卷：57
- 期：17
- 页码：7382-7395
- 全文大小：997K
- ISSN：1520-4804
文摘
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鈥揂ldrich 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.