The blockade of the programmed cell death protein 1/programmed cell death ligand\n1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune\nescape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by\nthe Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment.\nHowever, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral\nadministration, and immunogenicity, should not be overlooked. To overcome these disadvantages,\nsmall-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in\nsilico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the\ninhibition of PD-1â??PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1\nproteinâ??protein interface (PPI). Sequentially, we carried out virtual screening against our in-house\npeptide library to identify potential ligands. WANG-003,WANG-004, andWANG-005, three of our\nin-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted\nmolecular docking and molecular dynamics (MD) simulation for the further analysis of interactions\nbetween our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by\nsurface plasmon resonance (SPR) binding technology. The present study provides a new perspective\nfor the development of PD-1 inhibitors that disrupt PD-1â??PD-L1 interactions. These promising\npeptides have the potential to be utilized as a novel chemical probe for further studies, as well as\nproviding a foundation for further designs of potent small-molecule inhibitors targeting PD-1.
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