Constraining an Irregular Peptide Secondary Structure through Ring-Closing Alkyne Metathesis

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Peptide Therapeutics

Background:

• Macrocyclization enhances peptide drug properties like target affinity and stability.
• Current methods primarily stabilize alpha-helices, limiting applications for irregular peptide structures.
• Targeting challenging protein-protein interactions often requires novel peptide scaffolds.

Purpose of the Study:

• To explore ring-closing alkyne metathesis for stabilizing irregular peptide secondary structures.
• To develop novel macrocyclic peptides with improved affinity for protein targets.
• To investigate the structural basis of enhanced binding through crystallography.

Main Methods:

• Synthesis of alkyne-crosslinked peptides via ring-closing alkyne metathesis.
• Affinity assessment of macrocyclic peptide derivatives against the target protein.
• X-ray crystallography to determine the complex structure of the lead compound with 14-3-3ζ.

Main Results:

• Several alkyne-crosslinked peptide derivatives demonstrated enhanced target affinity compared to linear peptides.
• The crystal structure revealed the binding mode of the highest-affinity macrocycle with 14-3-3ζ.
• Successful stabilization of an irregular peptide secondary structure was achieved.

Conclusions:

• Ring-closing alkyne metathesis is a viable method for macrocyclizing irregular peptide structures.
• This approach yields novel peptide scaffolds with potential for targeting intractable proteins.
• The findings open new avenues for designing peptide therapeutics against challenging biological targets.