Biomimetic Design of Peptide Inhibitor to Block CD47/SIRPα Interactions
Si Zheng1, Yufan Ji1, Nanxing Li1
1Department of Biochemical Engineering and Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (MOE), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, People's Republic of China.
Abstract:
CD47 on the surface of tumor cells has become a research hot spot in immunotherapy and anticancer therapy, as it can bind to SIRPα protein on the surface of macrophages, which ultimately leads to immune escape of tumor cells. In the present study, molecular interactions between CD47 and human SIRPα proteins (including variant 1, V1 and variant 2, V2) were analyzed through molecular dynamics (MD) simulation and the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. Hydrophobic interactions were found as the main driving force for the binding of CD47 on SIRPα. The residues including pyroglutamate acid (Z)1, L2, E35, Y37, E97, L101, and T102 of CD47 were identified with a significant favorable contribution to the binding of CD47 on SIRPα (both V1 and V2). Based on this, a peptide inhibitor library with the sequence ZLXRTLXEXY was designed (X represents the arbitrary residue of 20 standard amino acids) and then screened using molecular docking, MD simulations, and experimental validation. Finally, a peptide ZLIRTLHEWY was determined with high affinity with SIRPα from 8000 candidates, containing 6/10 residues favorable for the binding on SIRPα V1 and 8/10 residues favorable for the binding on SIRPα V2, which was thus considered to have potential anticancer function.
Insights
Researchers identified key interactions between CD47 on tumor cells and SIRPα on macrophages. A novel peptide inhibitor, ZLIRTLHEWY, was designed to block this interaction, showing potential for anticancer therapy by enhancing immune response against tumors.
Area of Science:
- Immunology
- Molecular Biology
- Computational Chemistry
Background:
- CD47, a protein on tumor cells, facilitates immune evasion by binding to SIRPα on macrophages.
- Targeting the CD47-SIRPα interaction is a promising strategy for cancer immunotherapy.
Purpose of the Study:
- To analyze the molecular interactions between CD47 and human SIRPα (V1 and V2 variants).
- To design and validate a peptide inhibitor targeting the CD47-SIRPα interaction for potential anticancer applications.
Main Methods:
- Molecular dynamics (MD) simulations.
- Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations.
- Peptide library design, molecular docking, and experimental validation.
Main Results:
- Hydrophobic interactions are the primary driving force for CD47-SIRPα binding.
- Specific CD47 residues (Z1, L2, E35, Y37, E97, L101, T102) significantly contribute to binding.
- A high-affinity peptide inhibitor, ZLIRTLHEWY, was identified from 8000 candidates, showing strong binding to both SIRPα variants.
Conclusions:
- The identified peptide inhibitor demonstrates potential anticancer function by targeting the CD47-SIRPα pathway.
- This study provides a foundation for developing novel immunotherapies against cancer.
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