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Published on: December 1, 2020
In silico screening and surface plasma resonance-based verification of programmed death 1-targeted peptides
Pengli Zhang1, Chengping Li1, Xiaoyue Ji1
1School of Life Sciences, Zhengzhou University, Zhengzhou, China.
Abstract:
Programmed death 1 (PD-1) is a key immune checkpoint molecule. When it binds to programmed death-ligand 1 (PD-L1), it can negatively regulate the immune response. Therefore, blockade of the PD-1/PD-L1 interaction could unleash the power of immune system. Though successes achieved by anti-PD-1/PD-L1 antibody drugs in clinical for various cancers, many intrinsic limitations of the high molecular weight drugs require alternatives such as peptide drugs and chemical compounds. In this study, we described a novel in silico approach which was used to screen peptides from PDB database and aimed to identify peptides that have potential to bind the PD-L1 binding area of PD-1 molecule. Based on the docking poses, eight peptides were synthesized and measured for their binding abilities by surface plasma resonance technique. The KD values of the synthesized peptides ranged from 10.0 to 133.0 μM. Furthermore, the binding mechanism between PD-1 and the peptides was studied. In conclusion, we established a fast and reliable screening method for peptide discovery, which could be applied for identifying peptide inhibitors of various targets. The synthesized peptides could be served as starting points for designing PD-1 drug for cancer immunotherapy.
Insights
Researchers developed a new computational method to discover peptide inhibitors targeting the PD-1/PD-L1 pathway for cancer immunotherapy. This approach identified promising peptides that bind to PD-1, offering potential alternatives to antibody drugs.
Area of Science:
- Immunology
- Computational Biology
- Drug Discovery
Background:
- Programmed death 1 (PD-1) is a critical immune checkpoint that negatively regulates immune responses upon binding to programmed death-ligand 1 (PD-L1).
- Blocking the PD-1/PD-L1 interaction can enhance anti-tumor immunity, with antibody drugs showing clinical success in various cancers.
- Limitations of current antibody therapies necessitate the exploration of alternative therapeutic modalities, such as peptide-based drugs.
Purpose of the Study:
- To develop and validate a novel in silico screening approach for identifying peptides with potential to inhibit the PD-1/PD-L1 interaction.
- To discover novel peptide candidates that bind to the PD-1 molecule's PD-L1 binding site.
- To establish a foundation for developing peptide-based therapeutics for cancer immunotherapy.
Main Methods:
- Utilized a computational approach to screen the Protein Data Bank (PDB) database for peptides capable of binding to the PD-1 molecule.
- Performed molecular docking simulations to predict binding poses and identify potential peptide candidates.
- Synthesized eight selected peptides and experimentally validated their binding affinities to PD-1 using surface plasmon resonance (SPR).
Main Results:
- Identified eight peptides with varying binding affinities to PD-1, with dissociation constants (KD) ranging from 10.0 to 133.0 μM.
- Characterized the binding mechanisms between the synthesized peptides and the PD-1 molecule.
- Demonstrated the efficacy of the in silico screening method in identifying potential peptide inhibitors.
Conclusions:
- Established a rapid and reliable computational screening method for peptide discovery against various molecular targets.
- The identified peptides serve as promising starting points for the rational design of novel PD-1 inhibitors for cancer immunotherapy.
- This approach offers a viable alternative to traditional antibody-based therapies for modulating immune checkpoints.
