Targeting the tubulin C-terminal tail by charged small molecules

Li, Shuo; Mori, Mattia; Yang, Mingyan; Elfazazi, Soumia; Hortigüela, Rafael; Chan, P. S. H.; Feng, Xinyue; Risinger, April L.; Yang, Zhiyou; Oliva, M.A.; Díaz, J. Fernando; Fang, Wei‐Shuo

doi:10.1039/d2ob01910h

Cited by 2 publications

(2 citation statements)

References 39 publications

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“…One such example is the targeted covalent inhibitors that have shown promising activity against the intrinsically disordered protein, tau [ 166 ]. A very recent study involved the design of several peptides with multiple arginine residues that bind to negatively charged residues of the tubulin C-terminal tail [ 167 ]. The binding of these macrocyclic peptides to CTT caused the promotion of tubulin polymerization and the shortening of the nucleation phase [ 167 ].…”

Section: Challenges and Opportunitiesmentioning

confidence: 99%

“…A very recent study involved the design of several peptides with multiple arginine residues that bind to negatively charged residues of the tubulin C-terminal tail [ 167 ]. The binding of these macrocyclic peptides to CTT caused the promotion of tubulin polymerization and the shortening of the nucleation phase [ 167 ]. This study introduces a viable strategy for targeting the intrinsically disordered CTT of tubulin, that can inspire the development of new strategies for targeting the CTT of FtsZ.…”

Section: Challenges and Opportunitiesmentioning

confidence: 99%

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Models versus pathogens: how conserved is the FtsZ in bacteria?

et al. 2023

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Combating anti-microbial resistance by developing alternative strategies is the need of the hour. Cell division, particularly FtsZ, is being extensively studied for its potential as an alternative target for anti-bacterial therapy. Bacillus subtilis and Escherichia coli are the two well-studied models for research on FtsZ, the leader protein of the cell division machinery. As representatives of gram-positive and gram-negative bacteria respectively, these organisms have provided an extensive outlook into the process of cell division in rod-shaped bacteria. However, research on other shapes of bacteria, like cocci and ovococci, lags behind that of model rods. Even though most regions of FtsZ show sequence and structural conservation throughout bacteria, the differences in FtsZ functioning and interacting partners establishes several different modes of division in different bacteria. In this review, we compare the features of FtsZ and cell division in the model rods B. subtilis and E. coli and the four pathogens - Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis, and Pseudomonas aeruginosa. Reviewing several recent articles on these pathogenic bacteria, we have highlighted the functioning of FtsZ, the unique roles of FtsZ-associated proteins, and the cell division processes in them. Further, we provide a detailed look at the anti-FtsZ compounds discovered and their target bacteria, emphasizing the need for elucidation of the anti-FtsZ mechanism of action in different bacteria. Current challenges and opportunities in the ongoing journey of identifying potent anti-FtsZ drugs have also been described.

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Section: Challenges and Opportunitiesmentioning

confidence: 99%

Section: Challenges and Opportunitiesmentioning

confidence: 99%

Models versus pathogens: how conserved is the FtsZ in bacteria?

et al. 2023

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Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Vergoten,

Bailly

2024

Explor Drug Sci

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Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.

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Targeting the tubulin C-terminal tail by charged small molecules

Abstract: The disordered tubulin C-terminal tail (CTT), which possesses higher degree of heterogeneity, is the target for the interaction of many proteins and cellular components. Oppositely to the seven well-described binding...

Cited by 2 publications

References 39 publications

Models versus pathogens: how conserved is the FtsZ in bacteria?

Models versus pathogens: how conserved is the FtsZ in bacteria?

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

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