Structural Characterization of a Macrocyclic Peptide Modulator of the PD-1/PD-L1 Immune Checkpoint Axis

Zyla, Edyta; Musielak, Bogdan; Holak, Tad A.; Dubin, Grzegorz

doi:10.3390/molecules26164848

Cited by 6 publications

(3 citation statements)

References 23 publications

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“…Given the lacking of Fc fragments, peptides exhibited lower immunogenicity and better safety. Moreover, peptide ICIs are more stable in structure, and cost less in manufacture, storage, and drug administration ( 73 , 74 ). Even though, peptide ICIs have weaknesses including insufficient affinity, short body circulation, and a lack of tumor selectivity, which requires to be solved by suitable delivery systems.…”

Section: Nanotechnology Facilitates Immune Checkpoint Blockade Therapymentioning

confidence: 99%

Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology

Liu

Xiang²,

Zheng³

et al. 2022

Front. Immunol.

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Immune checkpoint blockade (ICB) has gained unparalleled success in the treatment of colorectal cancer (CRC). However, undesired side effects, unsatisfactory response rates, tumor metastasis, and drug resistance still hinder the further application of ICB therapy against CRC. Advancing ICB with nanotechnology can be game-changing. With the development of immuno-oncology and nanomaterials, various nanoplatforms have been fabricated to enhance the efficacy of ICB in CRC treatment. Herein, this review systematically summarizes these recent nano-strategies according to their mechanisms. Despite their diverse and complex designs, these nanoplatforms have four main mechanisms in enhancing ICB: 1) targeting immune checkpoint inhibitors (ICIs) to tumor foci, 2) increasing tumor immunogenicity, 3) remodeling tumor microenvironment, and 4) pre-sensitizing immune systems. Importantly, advantages of nanotechnology in CRC, such as innovating the mode-of-actions of ICB, modulating intestinal microbiome, and integrating the whole process of antigen presentation, are highlighted in this review. In general, this review describes the latest applications of nanotechnology for CRC immunotherapy, and may shed light on the future design of ICB platforms.

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Section: Nanotechnology Facilitates Immune Checkpoint Blockade Therapymentioning

confidence: 99%

Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology

Liu

Xiang²,

Zheng³

et al. 2022

Front. Immunol.

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“…The major interactions are contributed by G and F strands, whereas the interactions contributed by C and C′ strands are of lesser importance. 32 The matching structure is shown as Fig. 6.…”

Section: Peptide-based Small Molecule Inhibitorsmentioning

confidence: 99%

Progress in small-molecule inhibitors targeting PD-L1

Xu,

Kong,

Zhu

et al. 2024

RSC Med. Chem.

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“…Peptide and peptide-like substances have multiple advantages over mAbs, such as lower manufacturing costs and immunogenicity, higher stability, and more effective biological membrane penetration. − A D-form peptide that blocks the downstream signal of PD-1/PD-L1 was recently developed. − For instance, the D-form peptide DPPA-1 (NYSKPTDRQYHF) demonstrates a strong affinity for PD-L1 and can cross the cell membrane to block the PD-1/PD-L1 interaction. Preclinical trials have demonstrated that DPPA-1 can inhibit tumor growth and prolong life in experimental animals .…”

Section: Introductionmentioning

confidence: 99%

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

Tseng,

Lee,

Chen

et al. 2024

J. Chem. Inf. Model.

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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.

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Structural Characterization of a Macrocyclic Peptide Modulator of the PD-1/PD-L1 Immune Checkpoint Axis

Cited by 6 publications

References 23 publications

Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology

Advancing immune checkpoint blockade in colorectal cancer therapy with nanotechnology

Progress in small-molecule inhibitors targeting PD-L1

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

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