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Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin-inspired derivatives. The modest bioactivity and the apparent absence of interaction with α-tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α-tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p-Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

α-Synuclein is a presynaptic protein associated to Parkinson's disease, which is unstructured when free in the cytoplasm and adopts α helical conformation when bound to vesicles. After decades of intense studies, α-Synuclein physiology is still difficult to clear up due to its interaction with multiple partners and its involvement in a pletora of neuronal functions. Here, we looked at the remarkably neglected interplay between α-Synuclein and microtubules, which potentially impacts on synaptic functionality. In order to identify the mechanisms underlying these actions, we investigated the interaction between purified α-Synuclein and tubulin. We demonstrated that α-Synuclein binds to microtubules and tubulin α2β2 tetramer; the latter interaction inducing the formation of helical segment(s) in the α-Synuclein polypeptide. This structural change seems to enable α-Synuclein to promote microtubule nucleation and to enhance microtubule growth rate and catastrophe frequency, both in vitro and in cell. We also showed that Parkinson's disease-linked α-Synuclein variants do not undergo tubulin-induced folding and cause tubulin aggregation rather than polymerization. Our data enable us to propose α-Synuclein as a novel, foldable, microtubule-dynamase, which influences microtubule organisation through its binding to tubulin and its regulating effects on microtubule nucleation and dynamics.

Tubulin is a heterodimeric protein whose self assembly leads to the formation of protofilaments and of more complex structures called microtubules, key components of the cytoskeleton which have a fundamental role in the cell division process. Due to its biological function, tubulin is the target of many antitumoral molecules that exert their action on proliferating tumoral cells. Among these drugs, vinblastine has been widely used in therapy for a long time, albeit its mechanism of interaction with tubulin has remained elusive until recently. Vinblastine acts as a microtubule destabilizing agent and induces the formation of curved or ring-shaped tubulin polymers instead of linear protofilaments in vitro. In this paper we compare, using molecular dynamics simulations and free energy calculations, the network of interactions that allow the assembly of model linear protofilaments with those present in curved tubulin polymers complexed with vinblastine. It is shown that vinblastine, wedging between tubulin heterodimers, actually mediates part of the interactions between them and acts by crosslinking the two proteins, leading to the observed curved polymers rather than to their disassembly.

Microtubules are polymeric structures formed by the self-assembly of tubulin dimers. The growth and shrinkage of these dynamic arrays have a key role during the cell-proliferation process. This makes tubulin the molecular target of many anticancer drugs currently in use or under clinical trial. Their impressive success is limited by the onset of resistant tumour cells during the treatment, so new resistance-proof molecules need to be developed. Here we use molecular dynamics and free-energy calculations to study the network of interactions that allow microtubule formation. Modelling the protein-protein interface allows us to identify the amino acids responsible for tubulin-tubulin binding and thus to design peptides, which correspond to tubulin subsequences, that interfere with microtubule formation. We show that the application of molecular modelling techniques leads to the identification of peptides that exhibit antitubulin activity both in vitro and in cultured cells.

Epothilones are 16‐membered macrolides that act as microtubule‐targeting agents to tackle cancer. Many synthetic analogues have been investigated for their activity, yet often based on macrolide structures. A notable exception is Ixabepilone, an azalide whose metabolic stability and pharmacokinetics are significantly improved. Exploiting the amide‐triazole bioisosterism, in this work we report the synthesis of the first generation of epothilones lacking the macrolide or azalide structure, with the ester or amide linkage replaced by a triazole unit. Together with the synthesis of this new analogue, computational and biological evaluations have been performed too. [ABSTRACT FROM AUTHOR]

Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long‐chain derivatives and maytansinoid conjugates. We confirmed that bulky substituents do not impact their high activity or the scaffold's binding mode. These encouraging results open new avenues for the design of new maytansine‐based probes. [ABSTRACT FROM AUTHOR]

Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders. [ABSTRACT FROM AUTHOR]

The tree trunk is a microtubule, from which the tubulins are disassembling into the leaves. Keywords: chemical probes; maytansinoids; maytansinol functionalization; microtubules; tubulin EN chemical probes maytansinoids maytansinol functionalization microtubules tubulin 1 1 1 01/27/23 20230124 NES 230124 B Work with the elements of nature b : Our building block, maytansinol, represented as a constellation of stars, is the main protagonist of the story. [Extracted from the article]

Maytansinol, maytansine binding site, tubulin, microtubules, tubulin binders Keywords: maytansinol; maytansine binding site; tubulin; microtubules; tubulin binders EN maytansinol maytansine binding site tubulin microtubules tubulin binders 1 1 1 01/18/22 20220110 NES 220110 B The interdisciplinary character b of the Horizon2020-MSCA-EJD TubInTrain project allowed a challenging study of the peculiarity of maytansinoids as tubulin binders. [Extracted from the article]