Expanding Peptide Chemical Space via Acid-Mediated Arginine Modification

Area of Science:

• Chemical Biology
• Organic Chemistry
• Medicinal Chemistry

Background:

• Peptide modification is crucial for developing new therapeutics.
• Targeted modification of specific amino acid residues, like arginine, presents challenges.
• Arginine's guanidinium side chain offers unique chemical handles for modification.

Purpose of the Study:

• To develop a chemoselective method for modifying arginine residues in peptides.
• To create peptide derivatives with enhanced cellular permeability and drug-like properties.
• To establish a platform for late-stage diversification of modified peptides.

Main Methods:

• Acid-mediated reaction of peptides with malonaldehyde.
• Chemoselective conversion of arginine guanidinium side chains to amino pyrimidine moieties.
• Reversibility of side products using butylamine.
• Late-stage diversification of amino pyrimidine peptides.

Main Results:

• Near-quantitative conversion of arginine residues across diverse peptide substrates.
• Formation of stable amino pyrimidine moieties.
• Reversible side product formation demonstrating method robustness.
• Enhanced cellular permeability of modified peptides.
• Successful late-stage diversification into imidazo[1,2-a]pyrimidinium salts.

Conclusions:

• The described method provides efficient and chemoselective modification of arginine residues in peptides.
• The resulting amino pyrimidine peptides possess improved cellular permeability and drug-like characteristics.
• This strategy offers a versatile platform for expanding the chemical diversity of peptides for therapeutic applications.