2014
DOI: 10.1021/jm5008819
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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 l… Show more

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Cited by 29 publications
(39 citation statements)
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“…Modular variants of mycolactone were synthesized as described (20,23). Stock solutions of mycolactone and variants were prepared in dimethyl sulfoxide, and then diluted 1000× in culture medium for cellular assays or 10× in PBS before injection in animals.…”
Section: Methodsmentioning
confidence: 99%
See 1 more Smart Citation
“…Modular variants of mycolactone were synthesized as described (20,23). Stock solutions of mycolactone and variants were prepared in dimethyl sulfoxide, and then diluted 1000× in culture medium for cellular assays or 10× in PBS before injection in animals.…”
Section: Methodsmentioning
confidence: 99%
“…First, the chemical synthesis of this complex natural product is a costly, multistep process (1,(20)(21)(22), which challenges bulk industrial production. Second, whether mycolactone can be engineered to dissociate immunosuppression and analgesia from cytotoxicity is currently unknown (23)(24)(25). Here, we screened a large panel of structural variants of mycolactone in biochemical and cellular assays reflecting its biological activities.…”
Section: Introductionmentioning
confidence: 99%
“…Compound numbers are given in bold: <>, (Scherr et al ., ); {}, (Chany et al ., ); [], (Chany et al ., , Guenin‐Mace et al ., ).…”
Section: Structure‐function Studies Of Mycolactonementioning
confidence: 99%
“…One complication in understanding these data result from the fact that, in order to greatly simplify their synthesis, there is a whole class of mycolactone‐like molecules that lack the methyl group at C8 in the lactone core (so‐called C8‐desmethyl mycolactone) (Chany et al ., ; Chany et al ., ; Guenin‐Mace et al ., ). Compared with the ‘wild‐type’ molecule, this has reduced activity (the lowest dose with cytopathic activity is 5 μM and the IC 50 for IL‐2 is >4 μM vs. 40 nM for the ‘wild‐type’ molecule in both cases) and binds less well to WASP (IC 50 97 μM vs. 32 μM).…”
Section: Structure‐function Studies Of Mycolactonementioning
confidence: 99%
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