Late-stage peptide and protein modifications through phospha-Michael addition reaction

Area of Science:

• Biochemistry
• Organic Chemistry
• Chemical Biology

Background:

• Peptide and protein modification is crucial for drug development.
• Unprotected amino acids like dehydroalanine (Dha) present challenges for modification.
• Controlling protein aggregation is key for treating neurodegenerative diseases.

Purpose of the Study:

• To develop a versatile late-stage modification strategy for peptides and proteins.
• To utilize unprotected dehydroalanine (Dha) in modification reactions.
• To explore applications in enhancing peptide cell penetration and modulating protein aggregation.

Main Methods:

• Phospha-Michael addition reaction between functional phosphines and unprotected dehydroalanine (Dha).
• Application of the strategy to synthesize staple peptides.
• Utilizing the method to modify alpha-synuclein and study its aggregation.

Main Results:

• Successful late-stage modification of peptides and proteins under mild conditions.
• Generation of a staple peptide with enhanced cell membrane penetrability.
• Demonstrated regulation of alpha-synuclein aggregation properties and morphology via charge modification.

Conclusions:

• The developed phospha-Michael addition strategy offers a mild and effective method for peptide and protein functionalization.
• This approach enables the design of peptides with improved cellular uptake.
• The strategy provides a tool to modulate the aggregation behavior of disease-associated proteins like alpha-synuclein.