Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor

Qiao, Liang; Quan, Lina; Lyu, Jiankun; He, Zenghui; Wang, Xia; Meng, Jiajia; Zhao, Zhenjiang; Zhu, Lili; Liu, Xiaofeng; Li, Honglin

doi:10.18632/oncotarget.11274

Cited by 46 publications

(28 citation statements)

References 53 publications

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“…Another peptide inhibitor Ar5Y_4 was reported to target PD‐1, unlike the two peptides described above. Ar5Y_4 exhibits a binding affinity of ~1.38 μM for PD‐1 . It restores 67% of the Jurkat T cells’ production of IL‐2 but does so at a relatively high concentration of 250 μM, indicating that further optimization of this peptide structure is necessary to obtain more potent cellular activity .…”

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…Ar5Y_4 exhibits a binding affinity of ~1.38 μM for PD‐1 . It restores 67% of the Jurkat T cells’ production of IL‐2 but does so at a relatively high concentration of 250 μM, indicating that further optimization of this peptide structure is necessary to obtain more potent cellular activity . The goal was to design a peptide ligand for PD‐1 that incorporated five key hotspot residues derived from PD‐L1 (eg, Tyr56, Arg113, Ala121, Asp122, Tyr123 as determined by three in silico hotspot prediction tools) linked by different helices and scaffold fragments derived from a library.…”

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…To examine if these hotspot residues were responsible for the binding affinity of Ar5Y_4, alanine scanning was performed. Replacement of any of the residues with alanine resulted in a ~8 to 21‐fold reduction in the affinity of Ar5Y_4, suggesting that these residues are indeed necessary for binding to PD‐1 . Other peptides with varying combinations of hotspot residues on PD‐L1 (eg, Ala121, Asp122, and Tyr123; Arg113, Ala121, Asp122, Tyr123; Arg113, Met115, Ala121, Asp122, and Tyr123) were found to have lower binding affinity to PD‐1 than Ar5Y_4, with the K D ranging from ~3 to ~370 μM …”

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

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Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

153

121

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Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

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Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Small Molecule Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

153

121

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“…Many studies have been concerned with the design, synthesis, extraction, and evaluation of the effectiveness of such molecules. In recent years, peptide therapy has become one of the promise candidates for drug development in cancer treatment and other diseases [24,25,26,27,28,29,30,31,32]. Jolene L. Lau and Michael K. Dunn said that peptides represent one of the greatest areas of pharmaceutical development, particularly for tumor treatment, metabolic disease, and cardiovascular disease [33].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity

Abbas

Lin

Liu

et al. 2019

IJMS

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Immune-checkpoint blockades, suchas PD-1 monoclonal antibodies, have shown new promising avenues to treat cancers. Failure responsesof many cancer patients to these agents have led to a massive need for alternative strategies to optimize tumor immunotherapy. Currently, new therapeutic developments involve peptide blocking strategies, as they have high stability and low immunogenicity. Here, we have designed and synthesized a new peptide FITC-YT-16 to target PD-1. We have studied FITC-YT-16 by various experiments, including Molecular Operating Environment MOE modeling, purification testing by HPLC and LC mass, peptide/PD-1 conjugation and affinity by microscale thermophoresis (MST), and T cell immune-fluorescence imaging by fluorescence microscopy and flow cytometry. The peptide was tested for its ability to enhanceT cell activity against tumor cell lines, including TE-13, A549, and MDA-MB-231. Lastly, we assessed T cell cytotoxicity under peptide treatment. YT-16–PD-1 interaction showed a high binding affinity as a low energy complex that was confirmed by MOE. Furthermore, the peptide purity and molecular weights were 90.96% and 2344.66, respectively. MST revealed that FITC-YT-16 interacted with PD-1 at a Kd value of 17.8 ± 2.6 nM. T cell imaging and flow cytometry revealed high affinity of FITC-YT-16 to PD-1. Interestingly, FITC-YT-16 efficiently blocked PD-1 signaling pathways and promoted T cell inflammatory responses by elevating IL-2 and INF-γ levels. Moreover, FITC-YT-16 has the ability to activate T cell cytotoxicity. Therefore, FITC-YT-16 significantly enhanced T cell anti-tumor activity by blocking PD-1–PD-L1 interactions.

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“…The most potent peptide Ar5Y_4 had a K D value of 1.38 ± 0.39 µM, which was comparable to the binding affinity of the PD-L1. Ar5Y_4 showed the ability to interrupt the binding of PD-L1 to PD-1, providing a potential strategy for further optimization of PD-L1 peptide mimetics [74,81]. Smadbeck et al used a three-stage de novo peptide design approach to design EZH2 inhibitory peptides.…”

Section: De Novo Peptide Design Approachmentioning

confidence: 99%

Mimicking Strategy for Protein–Protein Interaction Inhibitor Discovery by Virtual Screening

Lei

Líu

et al. 2019

Molecules

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As protein–protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy toward the discovery of PPI inhibitors. In this review, we discuss recent advances in the application of virtual screening for identifying mimics of protein partners. The classification and function of the mimicking protein partner inhibitor discovery by virtual screening are described. We anticipate that this review would be of interest to medicinal chemists and chemical biologists working in the field of protein–protein interaction inhibitors or probes.

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Discovery of peptide inhibitors targeting human programmed death 1 (PD-1) receptor

Cited by 46 publications

References 53 publications

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Design and Synthesis of A PD-1 Binding Peptide and Evaluation of Its Anti-Tumor Activity

Mimicking Strategy for Protein–Protein Interaction Inhibitor Discovery by Virtual Screening

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