Issue 15, 2018

Iriomoteolides: novel chemical tools to study actin dynamics

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.

Graphical abstract: Iriomoteolides: novel chemical tools to study actin dynamics

Supplementary files

Article information

Article type
Edge Article
Submitted
02 Oct 2017
Accepted
10 Mar 2018
First published
03 Apr 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 3793-3802

Iriomoteolides: novel chemical tools to study actin dynamics

A. Unzue, R. Cribiú, M. M. Hoffman, T. Knehans, K. Lafleur, A. Caflisch and C. Nevado, Chem. Sci., 2018, 9, 3793 DOI: 10.1039/C7SC04286H

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements