Biomimetic design of inhibitors of immune checkpoint LILRB4

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.