Macrocyclization enhances affinity of chemokine-binding peptoids

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Molecular Biology

Background:

• Peptoids are versatile molecules capable of binding protein targets.
• Macrocyclization is a known technique to improve molecular rigidity and binding affinity.
• Interleukin-8 (CXCL8) is a key chemokine in inflammatory diseases.

Purpose of the Study:

• To develop a combined strategy for labeling and macrocyclizing peptoid sequences.
• To enhance the binding affinity of peptoids against the inflammatory chemokine CXCL8.
• To create a method applicable to various peptoid sequences.

Main Methods:

• Selection of hexameric peptoid sequences against CXCL8 using one-bead-one-compound libraries.
• On-bead macrocyclization of peptoid sequences with side-chain protecting groups.
• Tetramethylrhodamine labeling of the cyclized peptoid sequences.

Main Results:

• Successful labeling and macrocyclization of peptoid sequences targeting CXCL8.
• Macrocyclization increased the binding affinity of peptoids to CXCL8 by over an order of magnitude.
• The developed strategy is adaptable to a wide range of peptoid sequences.

Conclusions:

• The combined labeling and macrocyclization strategy effectively enhances peptoid affinity for protein targets.
• This approach offers a promising avenue for developing novel therapeutics for CXCL8-mediated inflammatory diseases.
• The method's versatility allows for broad application in peptoid-based drug discovery.