Discovery of Peptide-Based Tubulin Inhibitors Through Structure-Guided Design

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Tubulin is a critical target for cancer, antiparasitic, and neurodegenerative disease therapies.
• Existing tubulin-binding drugs face challenges like side effects, poor bioavailability, and limited specificity.
• Peptide-based therapies offer potential for improved selectivity and safety by modulating protein-protein interactions.

Purpose of the Study:

• To design and evaluate novel peptide-based agents targeting tubulin.
• To identify peptides with potent antimitotic activity and improved safety profiles.
• To explore structure-guided peptide design for microtubule-targeting agents.

Main Methods:

• Integrated computational-experimental approach.
• Molecular docking, molecular dynamics simulations, and MM-GBSA free energy calculations.
• Design and evaluation of 14 peptides derived from the αβ-tubulin dimer interface.

Main Results:

• NH2-P14-COOH demonstrated potent inhibition of tubulin polymerization (IC50 = 11.24 ± 3.82 μM).
• NH2-P14-COOH exhibited selective cytotoxicity against NCI-H1299 lung cancer cells (IC50 = 45.64 ± 3.20 μM).
• NH2-P14-COOH showed no significant toxicity to non-cancerous EA.hy926 cells (IC50 > 100 μM) and induced apoptosis.

Conclusions:

• NH2-P14-COOH is a selective antimitotic peptide with a favorable therapeutic index.
• Structure-guided peptide design is a viable strategy for developing novel microtubule-targeting agents.
• NH2-P14-COOH offers potential for reduced off-target toxicity in cancer therapy.