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Updated: Aug 15, 2026
07:21
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Dissecting Structural and Functional Determinants of Microtubules Stabilization through Guided Chemical Modulation
Francesca Bonato1,2, Rebeca París-Ogáyar1,3, Ahmed Soliman1,4
1Unit for the Development of Biological, Immunological and Chemical Drugs, Centro de Investigaciones Biológicas Margarita Salas - CSIC, Madrid28040.Spain.
Journal of Medicinal Chemistry
|August 13, 2026
Summary
Paclitaxel analogs can stabilize microtubules without causing harmful structural changes. This research separates microtubule stabilization from lattice modulation, revealing new insights into intracellular transport and motor protein dynamics.
Area of Science:
- Cell Biology
- Pharmacology
- Biochemistry
Background:
- Paclitaxel (PTX) stabilizes microtubules (MTs) but causes peripheral neuropathy, likely due to MT structural changes.
- Understanding how taxane derivatives affect MT architecture and function is crucial for developing safer therapeutics.
Purpose of the Study:
- To design and synthesize PTX analogs that decouple MT stabilization from adverse structural changes.
- To investigate how altered MT lattice architecture impacts motor protein and MAP dynamics.
Main Methods:
- Synthesis and characterization of novel PTX analogs.
- In vitro and cellular assays to assess MT stabilization and lattice structure.
- Live-cell imaging to track motor protein (dynein, kinesin-1) and MAP (Tau) dynamics.
Main Results:
- Compound 1b exhibited PTX-like MT stabilizing activity while preserving a native-like MT lattice.
- PTX-induced MT lattice expansion disrupted dynein retrograde transport and altered kinesin-1 motility.
- PTX suppressed dynamic Tau exchange, whereas 1b maintained more physiological Tau dynamics.
Conclusions:
- MT stabilization and lattice modulation are separable drug properties.
- Drug-induced MT structural states regulate intracellular transport and MAP behavior.
- This work provides a foundation for developing taxanes with reduced neurotoxicity.
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