Captides: rigid junctions between beta sheets and small molecules.

Area of Science:

• Chemical Biology
• Supramolecular Chemistry
• Peptide Chemistry

Background:

• Bioconjugation methods often result in flexible linkages between small molecules and peptides.
• Precisely controlling the spatial orientation of small molecules within peptide structures is challenging.
• Beta hairpin motifs offer a structured scaffold for precise molecular organization.

Purpose of the Study:

• To report a novel strategy for creating covalently linked small molecule-peptide adducts.
• To investigate the precise, rigid, and buried environment of small molecules within peptide structures.
• To demonstrate the general applicability of this strategy for various peptide sequences and small molecules.

Main Methods:

• Synthesis of small molecule-peptide adducts using standard solid-phase Fmoc chemistry.
• Utilizing terminally capped beta hairpin motifs and small molecule hubs with carboxylic acid groups.
• Characterization of the resulting adducts to confirm structure and rigidity.

Main Results:

• Successfully prepared a series of small molecule-peptide adducts with controlled structures.
• Demonstrated the ability to achieve precise and rigid orientation of small molecules within the peptide scaffold.
• Showcased the versatility of the method with a nine-residue 'captide' and applicability to beta-strand-terminating peptides.
• Confirmed that various small molecules bearing carboxylic acid groups can be incorporated.

Conclusions:

• The developed strategy provides fold-dependent rigidity, distinguishing it from existing bioconjugation techniques.
• This method enables precise control over the small molecule's environment and orientation.
• Potential applications include catalyst enhancement, drug design, higher-order assembly, and FRET calibration rulers.