Design, synthesis and biological evaluation of PD-1 derived peptides as inhibitors of PD-1/PD-L1 complex formation for cancer therapy

Bojko, Magdalena; Sikorska, Emilia; Kocikowski, Mikolaj; Parys, Maciej; Battin, Claire; Schmitz, Peter; Kogut, Małgorzata M.; Winnicki, Mikołaj; Sieradzan, Adam K.; Spodzieja, Marta; Rodziewicz‐Motowidło, Sylwia

doi:10.1016/j.bioorg.2022.106047

Cited by 12 publications

(11 citation statements)

References 75 publications

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“…The amino acids from the N-terminal and middle part of PD-L1 create notably fewer contacts with PD-1; the most important interactions are created by F19 L and K78 (−5.57 kcal/mol), D26 L and Q75 (−3.09 kcal/mol), Y56 L and A132 (−2.19 kcal/mol), and Q66 L and A132 (−1.95 kcal/mol). Moreover, A18 L strongly interacts with E84 (−9.80 kcal/mol), D85 (−2.06 kcal/mol), and R86 (−3.90 kcal/mol), while its per-residue energy decomposition is 3.46 kcal/mol; this finding indicates that it is unfavourable for protein complex formation [30] . The interactions between the individual amino acids in PD-L1 and PD-1 designated based on the crystal structure of the proteins and from pairwise per-residue energy decomposition are presented in Table S1.…”

Section: Resultsmentioning

confidence: 97%

“…The second fragment includes amino acid residues from the middle part of the protein, namely I54 L (−1.39 kcal/mol) and Y56 L (−2.74 kcal/mol). However, the amino acids with the lowest energy are mainly located in the C-terminal part of PD-L1; these include R113 L (−4.68 kcal/mol), M115 L (−2.35 kcal/mol), A121 L (−4.57 kcal/mol), D122 L (−1.75 kcal/mol), Y123 L (−3.30 kcal/mol), and R125 L (−6.31 kcal/mol) (Figure S1) [30] .…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, the crystal structure of the PD-1/PD-L1 protein complex (PDB: 4ZQK ) [24] and molecular mechanics-generalized Born surface area (MM/GBSA) analysis, which was previously performed by us [30] , were used to design peptides targeting PD-1. Three groups of compounds comprising three binding fragments of PD-L1 were synthesized and tested.…”

Section: Introductionmentioning

confidence: 99%

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

Bojko,

Węgrzyn,

Sikorska

et al. 2024

Translational Oncology

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Bojko,

Węgrzyn,

Sikorska

et al. 2024

Translational Oncology

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“…On the other hand, Bojko and co-workers [ 91 ] designed and synthetized potential blockers/inhibitors of the PD-1/PD-L1 pathway. The sequences of the peptides were based on the binding sites of PD-1 to PD-L1, as shown by the crystal structure of the complex, and also on molecular mechanics with generalized Born and surface area solvation (MM/GBSA).…”

Section: Computational Methods For Predicting Checkpoint Inhibitorsmentioning

confidence: 99%

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Sobral

Luz

Almeida

et al. 2023

IJMS

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Computational approaches in immune-oncology therapies focus on using data-driven methods to identify potential immune targets and develop novel drug candidates. In particular, the search for PD-1/PD-L1 immune checkpoint inhibitors (ICIs) has enlivened the field, leveraging the use of cheminformatics and bioinformatics tools to analyze large datasets of molecules, gene expression and protein–protein interactions. Up to now, there is still an unmet clinical need for improved ICIs and reliable predictive biomarkers. In this review, we highlight the computational methodologies applied to discovering and developing PD-1/PD-L1 ICIs for improved cancer immunotherapies with a greater focus in the last five years. The use of computer-aided drug design structure- and ligand-based virtual screening processes, molecular docking, homology modeling and molecular dynamics simulations methodologies essential for successful drug discovery campaigns focusing on antibodies, peptides or small-molecule ICIs are addressed. A list of recent databases and web tools used in the context of cancer and immunotherapy has been compilated and made available, namely regarding a general scope, cancer and immunology. In summary, computational approaches have become valuable tools for discovering and developing ICIs. Despite significant progress, there is still a need for improved ICIs and biomarkers, and recent databases and web tools have been compiled to aid in this pursuit.

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“…The protein-protein interactions (PPIs) of PD-1/PD-L1 complex occurs through two large (1970 Å2) and flat binding surfaces that are structurally defined by several β-strand and β-turn motifs, which provides proof of principle of mimicry approach for peptide inhibitors designing 36 . The molecular mechanics generalized Born surface area (MM/GBSA) analysis indicates that fragments N66-R86 and I126-E136 of PD-1 protein, and fragments I54-Y56 and R113-R125 of the PD-L1 protein are strongly involved in the interaction of both proteins 37 . The human PD-L1 and human PD-1 were confirmed to form a 1:1 complex in stoichiometry in both crystal and solution state 34 , 38 .…”

Section: Structure Functions and Regulation Of Pd-l1mentioning

confidence: 99%

Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

Yin¹,

Chen²,

Chen³

et al. 2023

Theranostics

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Immunotherapy has achieved great success recently and opened a new avenue for anti-tumor treatment. Programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) are typical immune checkpoints that transmit coinhibitory signals, muting the host immunity. Monoclonal antibodies that block PD-1/PD-L1 axis have benefited many patients with different tumor diseases. However, the objective response rate is still unsatisfactory. In this review, we summarize three strategies targeting PD-L1 based on different forms of PD-L1 and various regulating mechanisms to enhance the therapeutic effect, including blockade of the interaction between PD-L1 and PD-1, downregulation of PD-L1 expression and degradation of mature PD-L1. Thereinto, we describe a variety of materials have been designed to target PD-L1, including antibodies, nanoparticle, peptide, aptamer, RNA, and small molecule. Additionally, we list the drugs with PD-L1 regulation capacity used in clinical and ongoing studies to explore other alternatives for targeting PD-L1 besides anti-PD-L1 monoclonal antibodies. Moreover, we discuss associated opportunities for cancer combination therapy with other modalities such as chemotherapy, radiotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT), as these conventional or emerging modalities are capable of increasing the immune response of tumor cells by altering the tumor microenvironment (TME), and would display synergistic effect. At last, we give a brief summary and outlook regarding the research status and future prospect of immunotherapy.

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Design, synthesis and biological evaluation of PD-1 derived peptides as inhibitors of PD-1/PD-L1 complex formation for cancer therapy

Cited by 12 publications

References 75 publications

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

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

Computational Approaches Drive Developments in Immune-Oncology Therapies for PD-1/PD-L1 Immune Checkpoint Inhibitors

Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy

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