Targeting the tubulin C-terminal tail by charged small molecules

Shuo Li, Mattia Mori, Mingyan Yang, Soumia Elfazazi, Rafael Hortigüela, Peter Chan, Xinyue Feng, April Risinger, Zhiyou Yang, María Ángela Oliva, J. Fernando Díaz, Wei Shuo Fang

Research output: Contribution to journalArticlepeer-review


The disordered tubulin C-terminal tail (CTT), which possesses a higher degree of heterogeneity, is the target for the interaction of many proteins and cellular components. Compared to the seven well-described binding sites of microtubule-targeting agents (MTAs) that localize on the globular tubulin core, tubulin CTT is far less explored. Therefore, tubulin CTT can be regarded as a novel site for the development of MTAs with distinct biochemical and cell biological properties. Here, we designed and synthesized linear and cyclic peptides containing multiple arginines (RRR), which are complementary to multiple acidic residues in tubulin CTT. Some of them showed moderate induction and promotion of tubulin polymerization. The most potent macrocyclic compound 1f was found to bind to tubulin CTT and thus exert its bioactivity. Such RRR containing compounds represent a starting point for the discovery of tubulin CTT-targeting agents with therapeutic potential.

Original languageEnglish (US)
Pages (from-to)153-162
Number of pages10
JournalOrganic and Biomolecular Chemistry
Issue number1
StatePublished - Nov 28 2022

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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