A "cross-stitched" peptide with improved helicity and proteolytic stability

Area of Science:

• Computational chemistry
• Peptide design
• Structural biology

Background:

• Designing stable peptide structures is crucial for therapeutic applications.
• Understanding helix folding energy is key to predicting peptide conformation.
• Estrogen receptor alpha (ERα) is a significant target in various diseases.

Purpose of the Study:

• To develop a computational approach for quantitative helix folding energy profiles.
• To design novel orthogonal hydrocarbon and lactam bicyclic peptides.
• To evaluate the binding affinity and structural pose of designed peptides for ERα.

Main Methods:

• Utilized a new computational method to calculate quantitative energy profiles for helix folding.
• Employed peptide synthesis to create orthogonal hydrocarbon and lactam bicyclic peptides.
• Assessed binding affinity using nanomolar measurements and confirmed structural pose via X-ray crystallography.

Main Results:

• Successfully designed and synthesized proteolytically stable,
• cross-stitched
• bicyclic peptides.
• The peptide SRC2-BCP1 demonstrated nanomolar affinity for estrogen receptor α.
• X-ray crystallography confirmed a helical binding pose for SRC2-BCP1.

Conclusions:

• The new computational approach enables the design of conformationally constrained peptides.
• SRC2-BCP1 represents a promising candidate for ERα targeting due to its stability and high affinity.
• The study validates the utility of computational methods in designing peptides with specific structural and functional properties.