Autophagy inducing cyclic peptides constructed by methionine alkylation

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Drug Discovery

Background:

• Autophagy is a crucial cellular process implicated in various diseases.
• Developing effective and stable autophagy inducers is a significant challenge in drug discovery.
• Existing methods for peptide modification often lack efficiency and versatility.

Purpose of the Study:

• To design and synthesize novel peptide-based autophagy inducers with enhanced stability.
• To explore the utility of the methionine bis-alkylation method for generating diverse peptide macrocycles.
• To identify potent peptide candidates for modulating autophagy.

Main Methods:

• Employed a facile methionine bis-alkylation strategy for peptide macrocyclization.
• Synthesized a library of bicyclic peptides.
• Assessed autophagy-inducing activity and proteolytic resistance of the synthesized peptides.

Main Results:

• Generated peptides that induce autophagy at micromolar concentrations.
• Achieved improved proteolytic resistance in the designed peptides.
• Identified a short bicyclic peptide (7f) as the most potent autophagy inducer.

Conclusions:

• The methionine alkylation-based macrocyclization is a versatile method for generating peptide-based autophagy inducers.
• Peptide 7f represents a promising lead compound for further development as an autophagy modulator.
• This approach facilitates the diversity-oriented generation of stable and potent peptide therapeutics.