Iriomoteolides: novel chemical tools to study actin dynamics

TitleIriomoteolides: novel chemical tools to study actin dynamics
Publication TypeJournal Article
Year of Publication2018
AuthorsUnzue A., Cribiú R., Hoffman MM, Knehans T., Lafleur K., Caflisch A., Nevado C.
JournalChemical Science
Volume9
Start Page3793
Issue15
Pagination3793-3802
Date PublishedApr 21 2018
Type of ArticleResearch Article
Keywordsactin, cytoskeleton, Drug Discovery, iriomoteolides, natural products
Abstract

Despite its promising biological profile, the cellular targets of iriomoteolide-3a, a novel 15-membered macrolide isolated from Amphidinium sp., have remained unknown. A small library of non-natural iriomoteolide-3a analogues is presented here as a result of a novel, highly convergent, catalysis-based scaffold-diversification campaign, which revealed the suitable sites for chemical editing in the original core. We provide compelling experimental evidence for actin as one of iriomoteolides' primary cellular targets, establishing the ability of these secondary metabolites to inhibit cell migration, induce severe morphological changes in cells and cause a reversible cytoplasmic retraction and reduction of F-actin fibers in a time and dose dependent manner. These results are interpreted in light of the ability of iriomoteolides to stabilize F-actin filaments. Molecular dynamics simulations provide evidence for iriomoteolide-3a binding to the barbed end of G-actin. These results showcase iriomoteolides as novel and easily tunable chemical probes for the in vitro study of actin dynamics in the context of cell motility processes including cell invasion and division.

URLhttp://pubs.rsc.org/en/content/articlehtml/2018/sc/c7sc04286h
DOI10.1039/C7SC04286H
pubindex

0233

Alternate JournalChem. Sci.
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