Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for α-Helical Peptidomimetics

Area of Science:

• Medicinal Chemistry
• Peptide Science
• Drug Discovery

Background:

• Peptides and peptidomimetics are promising drug candidates due to target specificity and low toxicity.
• Existing stapling strategies like hydrocarbon (HC)-stapling enhance peptide stability but have limitations.
• Unnatural amino acids offer unique properties for peptide modification and stabilization.

Purpose of the Study:

• To introduce a novel noncovalent peptide stapling strategy utilizing the unnatural amino acid α-methyl-l-phenylalanine (αF).
• To design and synthesize a stabilized α-helical B-chain mimetic of human relaxin-3 (H3 relaxin).
• To evaluate the stability and biological function of the developed H3 relaxin B-chain mimetic.

Main Methods:

• Utilized α-methyl-l-phenylalanine (αF) for noncovalent peptide stapling.
• Synthesized an α-helical B-chain mimetic of human relaxin-3 (H3 relaxin), designated H3B10-27(13/17αF).
• Conducted comprehensive in vitro, ex vivo, and in vivo studies to assess stability and biological activity.

Main Results:

• The novel noncovalent stapling strategy successfully stabilized the peptide.
• The resulting H3 relaxin B-chain mimetic, H3B10-27(13/17αF), demonstrated remarkable stability in serum.
• The mimetic fully replicated the biological function of H3 relaxin.

Conclusions:

• The developed noncovalent stapling approach using αF is a high-yielding and effective method for peptide stabilization.
• H3B10-27(13/17αF) serves as an excellent scaffold for drug development and a tool for studying RXFP3 receptor function.