Translational Oncology (Apr 2024)

Peptide-based inhibitors targeting the PD-1/PD-L1 axis: potential immunotherapeutics for cancer

  • Magdalena Bojko,
  • Katarzyna Węgrzyn,
  • Emilia Sikorska,
  • Piotr Ciura,
  • Claire Battin,
  • Peter Steinberger,
  • Katarzyna Magiera-Mularz,
  • Grzegorz Dubin,
  • Adam Kulesza,
  • Adam K. Sieradzan,
  • Marta Spodzieja,
  • Sylwia Rodziewicz-Motowidło

Journal volume & issue
Vol. 42
p. 101892

Abstract

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The PD-1/PD-L1 complex belongs to the group of inhibitory immune checkpoints and plays a critical role in immune regulation. The PD-1/PD-L1 axis is also responsible for immune evasion of cancer cells, and this complex is one of the main targets of immunotherapies used in oncology. Treatment using immune checkpoint inhibitors is mainly based on antibodies. This approach has great therapeutic potential; however, it also has major drawbacks and can induce immune-related adverse events. Thus, there is a strong need for alternative, non-antibody-based therapies using small molecules, peptides, or peptidomimetics. In the present study, we designed, synthesized, and evaluated a set of PD-1-targeting peptides based on the sequence and structure of PD-L1. The binding of these peptides to PD-1 was investigated using SPR and ELISA. We also assessed their ability to compete with PD-L1 for binding to PD-1 and their inhibitory properties against the PD-1/PD-L1 complex at the cellular level. The best results were obtained for the peptide PD-L1(111–127)(Y112C-I126C), named (L11), which displaced PD-L1 from binding to PD-1 in the competitive assay and inhibited the formation of the PD-1/PD-L1 complex. The (L11) peptide also exhibited strong affinity for PD-1. NMR studies revealed that (L11) does not form a well-defined secondary structure; however, MD simulation indicated that (L11) binds to PD-1 at the same place as PD-L1. After further optimization of the structure, the peptide inhibitor obtained in this study could also be used as a potential therapeutic compound targeting the PD-1/PD-L1 axis.

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