Author: Gago, Federico ; Northcote, Peter ; Bargsten, Katja ; Prota, Andrea E ; Kamimura, Shinji ; Giménez-Abián, Juan Francisco ; Bonato, Francesca ; Altmann, Karl-Heinz ; Díaz, J Fernando ; Van der Eycken, Johan ; Menche, Dirk ; Estévez-Gallego, Juan ; Steinmetz, Michel O ; Wullschleger, Christoph ; Lucena-Agell, Daniel ; Paterson, Ian ; Raes, Olivier ; Álvarez-Bernad, Beatriz ; Pera, Benet ; Cornelus, Jelle ; Oliva, María Ángela ; Martínez, Juan Carlos

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.

22 Nov 2021·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

On the Microtubule-Stabilizing Properties of a Tau Oligopeptide

Q2 · CHEMISTRY

Article

Author: Jiménez, Verónica A.

Preserving the integrity of neuronal microtubules (MTs) has emerged as a promising strategy to inhibit the progression of neurodegenerative disorders such as Alzheimer's disease. Such a goal could be achieved by peptides that mimic the functional role of Tau, an MT-associated protein that stabilizes MTs by dynamically binding to their outer surface. This work examines the binding properties and MT-stabilizing potential of a 27-amino acid Tau oligopeptide from 300 ns Gaussian-accelerated molecular dynamics simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations on octameric MT models bound to two equivalent and independent Tau peptides. Bound peptides adopted extended conformations that are highly consistent with cryo-electron microscopy reports for full-length Tau bound to MTs. Anchoring points in three consecutive tubulin subunits were identified, with a relevant contribution of the Ser419-Val435 region to α-tubulin. Tau peptides strengthen the longitudinal protein-protein contacts within the MT lattice and exert a cooperative MT-stabilizing effect in MT complexes simultaneously bonded to taxol or peloruside A. Ser phosphorylation results in a larger peptide mobility, altered interaction profiles, and MT destabilization, which are in line with the loss of MT integrity resulting from the post-translational hyperphosphorylation of Tau. Our results shed light on the MT-stabilizing potential of Tau-mimetic peptides to act as novel neuroprotective agents targeting MTs.

31 Mar 2021·Journal of Biomolecular Structure and Dynamics

Exploring the interaction of Peloruside-A with drug resistant αβII and αβIII tubulin isotypes in human ovarian carcinoma using a molecular modeling approach

Article

Author: Bhandare, Vishwambhar Vishnu ; Kumbhar, Bajarang Vasant

Microtubules (MTs) play an essential role in mitosis; hence they are identified as potential targets to design novel anti-mitotic agents. MT's are composed of α/β-tubulin isotypes that are associated with differential drug-resistant effects against MT-targeting agents. Peloruside-A (PLA) is a potent anti-mitotic agent showing excellent activity against taxol-resistant carcinoma. PLA alters MT dynamics by binding to the 'non-taxoid' site of β-tubulin. The abundance of βII and βIII tubulin isotypes in human ovarian carcinoma affects the efficacy of PLA. Nevertheless, the mechanism of PLA resistance due to βII and βIII tubulin isotype is not well understood. Therefore, we investigated the interactions of PLA with αβIIa, αβIIb, and αβIII tubulin isotypes which are predominantly expressed in the human ovarian carcinoma, using a molecular modeling approach. A sequence analysis study shows that the βIII isotype has seven residue variations at the 'non-taxoid' site compared to the βIIa and βIIb isotypes. Molecular docking and molecular dynamics simulation revealed that residue variation at the 'non-taxoid' site of βIII isotype affect PLA binding. Furthermore, binding energy calculations showed that αβIIa has the highest binding towards PLA, whereas αβIIb and αβIII isotypes shows weaker associations with PLA. Our computational study provides valuable structural and energetic information to increase understanding into the origin of PLA resistance in human ovarian carcinoma and could be helpful to develop potential PLA analogs against specific β-tubulin isotypes expressed in cancer cells.Communicated by Ramaswamy H. Sarma.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	Victoria University of Wellington	-

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