Development of Glycosylation-Modified DPPA-1 Compounds as Innovative PD-1/PD-L1 Blockers: Design, Synthesis, and Biological Evaluation

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 8; p. 1898
• Main Authors: Deng, Peng, Dong, Xiaodan, Wu, Ziyuan, Hou, Xixi, Mao, Longfei, Guo, Jingjing, Zhao, Wenshan, Peng, Chune, Zhang, Zhe, Peng, Lizeng
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 22.04.2024
• Subjects: Binding sites; cancer immunotherapy; Cancer therapies; Dendritic cells; Drug development; Drugs; Glycoproteins; glycosylation; Hydrogen bonds; immune checkpoint; Lymphocytes; Medical research; PD-1/PD-L1; peptide; Peptides; Physiology; Proteins; Toxicity
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29081898

In the context of peptide drug development, glycosylation plays a pivotal role. Accordingly, L-type peptides were synthesized predicated upon the PD-1/PD-L1 blocker DPPA-1. Subsequent glycosylation resulted in the production of two distinct glycopeptides, D-glu-LPPA-1 and D-gal-LPPA-1, by using D-glucose (D-glu) and D-galactose (D-gal), respectively, during glycosylation. Both glycopeptides significantly inhibited the interaction between PD-1 and PD-L1, and the measured half maximal inhibitory concentrations (IC50s) were 75.5 μM and 101.9 μM for D-glu-LPPA-1 and D-gal-LPPA-1, respectively. Furthermore, D-gal-LPPA-1 displayed a pronounced ability to restore T-cell functionality. In an MC38 tumor-bearing mouse model, D-gal-LPPA-1 demonstrated a significant inhibitory effect. Notably, D-gal-LPPA-1 substantially augmented the abundance and functionality of CD8+ T cells in the tumor microenvironment. Additionally, in the lymph nodes and spleens, D-gal-LPPA-1 significantly increased the proportion of CD8+ T cells secreting interferon-gamma (IFN-γ). These strong findings position D-gal-LPPA-1 as a potent enhancer of the antitumor immune response in MC38 tumor-bearing mice, underscoring its potential as a formidable PD-1/PD-L1 blocking agent.