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Spatiotemporal Subcellular Manipulation of the Microtubule Cytoskeleton in the Living Preimplantation Mouse Embryo using Photostatins
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Tools for the rational design of bivalent microtubule-targeting drugs

Jacopo Marangon1, Michael S Christodoulou2, Fancesca V M Casagrande1

  • 1Dipartimento di Bioscienze, Università degli Studi di Milano, via Celoria 26, 20133 Milano, Italy.

Biochemical and Biophysical Research Communications
|September 11, 2016
PubMed

Insights

Microtubule-targeting bivalent compounds (MTBCs) show poor efficacy. This study investigates why, using thiocolchine and its dimers, offering insights for rational MTBC drug design for cancer and neurodegenerative diseases.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Structural Biology

Background:

  • Microtubule (MT) dynamics are crucial drug targets for cancer chemotherapy and neurodegenerative diseases.
  • While drug combinations can enhance efficacy, bivalent MT-targeting compounds (MTBCs) often underperform their monomeric counterparts.
  • Understanding the reasons behind MTBCs' limited efficacy is essential for developing improved therapeutics.

Purpose of the Study:

  • To investigate the performance of MTBCs by characterizing prototype molecules: thiocolchine (TH) and two bivalent TH-homodimers.
  • To elucidate the chemical and structural factors influencing the efficacy of MTBCs.
  • To provide a basis for the rational design of more effective MTBCs.

Main Methods:

  • Binding affinity assays to quantify molecular interactions.
  • X-ray crystallography to determine the structural complex of tubulin with TH.
  • Molecular dynamics simulations to interpret binding affinities and molecular behavior.
  • Cell-based assays on HeLa cells to assess effects on MT cytoskeleton and cell survival.

Main Results:

  • Characterization of binding affinities for TH and its bivalent homodimers.
  • Structural insights into tubulin-TH complex formation.
  • Correlation of binding affinities with structural data and simulation results.
  • Validation of cellular effects on MT cytoskeleton and cell viability.

Conclusions:

  • The study provides a comprehensive analysis of MTBC performance, highlighting structural and chemical factors.
  • Findings offer critical considerations for the rational design of novel MTBCs with enhanced therapeutic potential.
  • This research contributes to the development of improved MT-targeting agents for cancer and neurodegenerative diseases.
Keywords:
Drug designMicrotubule-binding agentsMicrotubulesThiocolchicineTubulin structure

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