A non-hydrolysable peptidomimetic for mitochondrial targeting

Area of Science:

• Biomaterials Science
• Cell Biology
• Medicinal Chemistry

Background:

• Peptidomimetics offer improved stability and bioavailability over natural peptides.
• Mitochondria are key therapeutic targets in various disorders.
• Cationic and hydrophobic amino acid-rich peptides naturally target mitochondria.

Purpose of the Study:

• To develop and characterize a novel hybrid γ,γ-peptidomimetic for efficient mitochondrial targeting.
• To assess the peptidomimetic's stability, biocompatibility, and targeting efficiency in living cells.
• To explore its utility in tracking mitochondrial dynamics and monitoring mitochondrial pH.

Main Methods:

• Synthesized a hybrid γ,γ-peptidomimetic scaffold with alternating non-natural amino acids.
• Evaluated membrane translocation, mitochondrial targeting, and biocompatibility in cellular models.
• Assessed stability against proteases and serum degradation.
• Utilized the peptidomimetic to track mitochondrial dynamics and deliver a pH probe.

Main Results:

• The peptidomimetic demonstrated efficient membrane translocation and selective mitochondrial targeting.
• Mitochondrial targeting was dependent on the electron transport chain's electrochemical potential.
• The compound exhibited exceptional stability in biological media, resisting protease degradation for over a week.
• Enabled precise tracking of mitochondrial fission and movement, and facilitated pH monitoring.

Conclusions:

• Introduced a highly stable, mitochondria-targeting peptidomimetic with significant biomedical potential.
• The scaffold's stability and targeting efficiency allow for detailed study of mitochondrial processes.
• This peptidomimetic serves as a valuable tool for investigating mitochondrial function and disease.