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Biomimetic design of inhibitors of immune checkpoint LILRB4
1Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.
Insights
Researchers explored interactions between leukocyte immunoglobulin-like receptor B4 (LILRB4) and an antibody to design peptide inhibitors. This study identified key binding residues and developed novel peptide inhibitors for potential acute myeloid leukemia (AML) therapies.
Area of Science:
- Immunology
- Biochemistry
- Computational Biology
Background:
- Immune checkpoint inhibitors are a key focus for acute myeloid leukemia (AML) treatment.
- Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint target.
- Understanding LILRB4 interactions is crucial for developing novel AML therapies.
Purpose of the Study:
- To investigate the molecular interactions between LILRB4 and its monoclonal antibody (mAb) h128-3.
- To computationally design and validate peptide inhibitors targeting LILRB4.
- To advance therapeutic strategies for acute myeloid leukemia.
Main Methods:
- Molecular dynamics (MD) simulations were employed to analyze LILRB4-mAb interactions.
- Molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) was used to identify key binding residues.
- Molecular docking and MD simulations were utilized for peptide inhibitor screening and validation.
Main Results:
- Hydrophobic interactions were identified as the primary driving force for mAb h128-3 binding to LILRB4.
- Key amino acid residues involved in the binding were pinpointed.
- Two novel peptide inhibitors, SADHYHSY and SVDWYHSY, were designed and validated for their ability to block LILRB4.
Conclusions:
- The study provides molecular insights into LILRB4-mAb interactions.
- Novel peptide inhibitors targeting LILRB4 were successfully developed.
- These findings support the development of new therapies for acute myeloid leukemia.
Abstract:
Immune checkpoint inhibitors have become a hot spot in the treatment of acute myeloid leukemia (AML), the most common acute leukemia (blood cancer) in adults. In the present study, molecular insights into the molecular interactions between an immune checkpoint leukocyte immunoglobulin-like receptor b4 (LILRB4) and its mAb h128-3 was explored using molecular dynamics (MD) simulation for the biomimetic design of peptide inhibitor of LILRB4. Both hydrophobic interaction and electrostatic interaction were found favorable for the binding of the mAb h128-3 on LILRB4, and hydrophobic interaction was identified as the main driving force. The key amino acid residues for the binding of mAb h128-3 on LILRB4 were identified as Y93, D94, D106, Y34, S103, W107, Y61, N30, E27, Y33, Y59, W95, S92 through MM-PBSA (molecular mechanics-Poisson-Boltzmann surface area) method. Based on this, an inhibitor library with the sequence of SXDXYXSY (Where X is an arbitrary amino acid residue) were designed. Two peptide inhibitors, SADHYHSY and SVDWYHSY were obtained through screening using molecular docking and MD simulations, and then validated by successful blocking of LILRB4 through the covering of LILRB4 surface by these inhibitors. These results would be helpful for the research and development of therapies for AML.
