Structure-Guided Discovery of PD-1/PD-L1 Interaction Inhibitors: Peptide Design, Screening, and Optimization via Computation-Aided Phage Display Engineering.

Abstract

Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 μM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 μM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.

• Authors: Tien-Sheng Tseng, Chao-Chang Lee, Po-Juei Chen, Chiu-Yuen Lin, Wang-Chuan Chen, Yu-Ching Lee, Jiun-Han Lin, Kaun-Wen Chen, Keng-Chang Tsai
• Journal: Journal of chemical information and modeling (J Chem Inf Model) Vol. 64 Issue 5 Pg. 1615-1627 (Mar 11 2024) ISSN: 1549-960X [Electronic] United States
• PMID: 38356220 (Publication Type: Journal Article)

Chemical References

• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• B7-H1 Antigen
• Peptides

Topics

• Humans
• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor (chemistry)
• B7-H1 Antigen (chemistry)
• Peptides (pharmacology, chemistry)
• Neoplasms
• Bacteriophages (metabolism)