Chemical modulation of microtubule structure through the laulimalide/peloruside site.

Abstract

Taxanes are microtubule-stabilizing agents used in the treatment of many solid tumors, but they often involve side effects affecting the peripheral nervous system. It has been proposed that this could be related to structural modifications on the filament upon drug binding. Alternatively, laulimalide and peloruside bind to a different site also inducing stabilization, but they have not been exploited in clinics. Here, we use a combination of the parental natural compounds and derived analogs to unravel the stabilization mechanism through this site. These drugs settle lateral interactions without engaging the M loop, which is part of the key and lock involved in the inter-protofilament contacts. Importantly, these drugs can modulate the angle between protofilaments, producing microtubules of different diameters. Among the compounds studied, we have found some showing low cytotoxicity and able to induce stabilization without compromising microtubule native structure. This opens the window of new applications for microtubule-stabilizing agents beyond cancer treatment.

• Authors: Juan Estévez-Gallego, Beatriz Álvarez-Bernad, Benet Pera, Christoph Wullschleger, Olivier Raes, Dirk Menche, Juan Carlos Martínez, Daniel Lucena-Agell, Andrea E Prota, Francesca Bonato, Katja Bargsten, Jelle Cornelus, Juan Francisco Giménez-Abián, Peter Northcote, Michel O Steinmetz, Shinji Kamimura, Karl-Heinz Altmann, Ian Paterson, Federico Gago, Johan Van der Eycken, J Fernando Díaz, María Ángela Oliva
• Journal: Structure (London, England : 1993) (Structure) Vol. 31 Issue 1 Pg. 88-99.e5 (01 05 2023) ISSN: 1878-4186 [Electronic] United States
• PMID: 36462501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• laulimalide
• Lactones
• Tubulin
• Excipients

Topics

• Lactones (pharmacology)
• Tubulin (metabolism)
• Excipients (analysis, metabolism)
• Binding Sites
• Microtubules (metabolism)