Rational design and development of a peptide inhibitor for the PD-1/PD-L1 interaction

Boohaker, Rebecca J.; Sambandam, Vijaya; Segura, Isaac; Miller, Janis M.; Suto, Mark J.; Xu, Bo

doi:10.1016/j.canlet.2018.04.031

Cited by 36 publications

(43 citation statements)

References 22 publications

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“…The compound is currently in phase 1 clinical trials in patients with mesothelioma. 91 , 143 In addition, many PD-1 inhibitors are also under study.…”

Section: Prospectsmentioning

confidence: 99%

<p>Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy</p>

Chen

Hao

et al. 2020

DDDT

112

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PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.

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“…The compound is currently in phase 1 clinical trials in patients with mesothelioma. 91 , 143 In addition, many PD-1 inhibitors are also under study.…”

Section: Prospectsmentioning

confidence: 99%

<p>Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy</p>

Chen

Hao

et al. 2020

DDDT

112

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“…Replacing the L-amino acids with D-amino acids can improve the stability and oral bioavailability of these drugs. Another more recently developed peptide, PL120131, was designed to interact with the PD-1 molecule, based on the interacting residues on PD-L1 from the amino acid glycine at position 120 to asparagine at position 131 [101]. PL120131 was shown to act as a competitive inhibitor of PD-L1 by associating with the binding groove on PD-1, and to reverse the apoptotic signal induced by soluble PD-L1 in Jurkat cells and primary lymphocytes.…”

Section: Peptide Checkpoint Inhibitorsmentioning

confidence: 99%

Structure and Optimization of Checkpoint Inhibitors

Picardo

Doi

Hansen

2019

Cancers

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With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

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“…48 Inspections of the PD-1/PD-L1 structures show that a competitive inhibitor could be designed to fit into the PD-1/PD-L1 binding sites containing interacting residues spanning the methionine at the position 64 to the lysine at position 78 in PD-1 (PD64-78: Ac-MLNWNRLSPSNQTEK-NH2) and from the glycine at the position 120 to the asparagine at the position 131 in PD-L1 (PL120-131: Ac-GADYKRITVKVN-NH2). 86 Using the technology of mirror-image phage display, the first hydrolysis-resistant peptide antagonists synthesised with dextran amino acids were developed to target the PD-1/PD-L1 pathway. 87 The optimised D-PPA-1 peptide bound PD-L1 at an affinity of 0.51 μmol/L in vitro and inhibited the PD-1/PD-L1 interaction in vivo in mice.…”

Section: Pd -L1 Phos Phoryl Ation Palmitoyl Ation Intr Acellul mentioning

confidence: 99%

“…87 Using biolayer interferometry and in silico docking simulations, the PD-L1 peptide mimetic (PL120131) has been shown to interfere with the PD-1/PD-L1 interaction by binding to PD-1, inhibiting PD-1 mediated apoptotic signalling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. 86 Allowing for CTL anti-tumour activity, PL120131 sustained the co-culture survivability and activity of T-cells in a 3D co-culture model better than the anti-PD-1 blocking antibody. 86 Using a computational de novo peptide design method for peptides potentially to bind PD-1, the peptide Ar5Y_4 with a Kd value of 1.38 ± 0.39 μmol/L, which is comparable to the Kd value of the cognate PD-L1, inhibits the binding of PD-L1 to PD-1 and restores the function of suppressed Jurkat T-cells.…”

Section: Pd -L1 Phos Phoryl Ation Palmitoyl Ation Intr Acellul mentioning

confidence: 99%

“…86 Allowing for CTL anti-tumour activity, PL120131 sustained the co-culture survivability and activity of T-cells in a 3D co-culture model better than the anti-PD-1 blocking antibody. 86 Using a computational de novo peptide design method for peptides potentially to bind PD-1, the peptide Ar5Y_4 with a Kd value of 1.38 ± 0.39 μmol/L, which is comparable to the Kd value of the cognate PD-L1, inhibits the binding of PD-L1 to PD-1 and restores the function of suppressed Jurkat T-cells. 88 In addition by bacterial surface display methods for peptides that bind PD-L1, targeting PD-L1 peptide (TPP-1) was identified and verified to interfere with the interaction of PD-1/PD-L1 by a T-cell activation assay and mixed lymphocyte reaction.…”

Section: Pd -L1 Phos Phoryl Ation Palmitoyl Ation Intr Acellul mentioning

confidence: 99%

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Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

Wang

et al. 2019

Clin Exp Pharma Physio

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Summary Recent clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein‐1/PD‐1 ligand 1 (PD‐1/PD‐L1) has initiated a new era in the treatment of metastatic cancer. However, greater challenges remain to treat all cancers. The molecular architecture in the immune synapse constituting positive engagements for immune activation and negative checkpoints against immune hyperactivity is regulated dynamically by interaction between proteostasis and tumour microenvironment. This article reviews recent progresses in our understandings of the cellular and molecular mechanisms of the negative checkpoint PD‐1/PD‐L1 behaviours in immune tolerance of tumourigenesis and metastasis. We provide an overview on PD‐L1 gene expression regulation, protein turnover, intra‐ and extracellular trafficking, exosome‐mediated inter‐cellular transport, molecular interface peptide mimetics, inhibitory chemical compounds such as metformin, and antibody dynamics. We summarise PD‐L1 post‐translational modifications including glycosylation, palmitoylation, phosphorylation and ubiquitination, reflecting future research directions and opportunities in identifying tumour‐specific signalling targets, their regulatory molecules and pathways for intervention into various types of cancers.

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Rational design and development of a peptide inhibitor for the PD-1/PD-L1 interaction

Cited by 36 publications

References 22 publications

<p>Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy</p>

<p>Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy</p>

Structure and Optimization of Checkpoint Inhibitors

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

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