Persistent Membrane-Anchored Oligomeric Peptides with Nanopore Formation for Targeted Immune Modulation

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Off-target effects of recognition molecules are a major challenge in targeted diagnosis and therapy.
• Developing specific molecular structures to minimize these effects is crucial for effective treatment.

Purpose of the Study:

• To design and identify novel oligomeric helical peptides that overcome the challenge of off-target effects.
• To develop a peptide that specifically targets PD-L1 and enhances immunotherapy.

Main Methods:

• Rational design and high-throughput screening of oligomeric helical peptides.
• Amino acid mutations and structural optimizations to identify lead candidates (TA03 and TA10).
• Characterization of TA03's interaction with tumor cell membranes and PD-L1.

Main Results:

• TA03 was identified as a lead candidate specifically recognizing the PD-L1 target.
• TA03 forms stable "hourglass-like" nanopores on tumor cell membranes via aromatic-hydrophobic interactions of tryptophan residues.
• This structure ensures prolonged residence time, persistent PD-L1 interaction, and avoidance of off-target effects.
• TA03 physically disrupts tumor cells, boosting immunotherapy and inhibiting tumor growth.

Conclusions:

• Novel oligomeric helical peptides, exemplified by TA03, can overcome off-target effects for membrane-associated targets.
• TA03's unique structure and PD-L1 targeting offer a promising strategy for enhanced cancer immunotherapy.
• This approach provides a new avenue for designing molecular structures to improve targeted therapies.