scholarly journals In vitro characterization of a small molecule PD-1 inhibitor that targets the PD-l/PD-L1 interaction

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chih-Hao Lu ◽  
Wei-Min Chung ◽  
Chun-Hao Tsai ◽  
Ju-Chien Cheng ◽  
Kai-Cheng Hsu ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Small Molecule ◽  
Inhibitory Activity ◽  
Small Molecule Inhibitors ◽  
Interleukin 2 ◽  
Jurkat Cells ◽  
Soluble Form ◽  
Organ Systems

AbstractTargeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis with monoclonal antibodies (mAbs) represents a crucial breakthrough in anticancer therapy, but mAbs are limited by their poor oral bioavailability, adverse events in multiple organ systems, and primary, adaptive, and acquired resistance, amongst other issues. More recently, the advent of small molecule inhibitors that target the PD-1/PD-L1 axis have shown promising cellular inhibitory activity and the potential to counteract the disadvantages of mAbs. In this study, structure-based virtual screening identified small molecule inhibitors that effectively inhibited the PD-1/PD-L1 interaction. Six of those small molecule inhibitors were applied to cell-based experiments targeting PD-1: CH-1, CH-2, CH-3, CH-4, CH-5, and CH-6. Of all 6, CH-4 displayed the lowest cytotoxicity and strongest inhibitory activity towards the PD-1/PD-L1 interaction. The experiments revealed that CH-4 inhibited the interaction of soluble form PD-L1 (sPD-L1) with PD-1 surface protein expressed by KG-1 cells. Investigations into CH-4 analogs revealed that CH-4.7 effectively blocked the PD-1/sPD-L1 interaction, but sustained the secretion of interleukin-2 and interferon-γ by Jurkat cells. Our experiments revealed a novel small molecule inhibitor that blocks the interaction of PD-1/sPD-L1 and potentially offers an alternative PD-1 target for immune checkpoint therapy.

scholarly journals PD-1-Targeted Discovery of Peptide Inhibitors by Virtual Screening, Molecular Dynamics Simulation, and Surface Plasmon Resonance

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3784 ◽  
Author(s):  
Yuanqiang Wang ◽  
Haiqiong Guo ◽  
Zhiwei Feng ◽  
Siyi Wang ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cell Death ◽  
Surface Plasmon Resonance ◽  
Virtual Screening ◽  
Programmed Cell Death ◽  
Surface Plasmon ◽  
Small Molecule ◽  
Plasmon Resonance ◽  
Small Molecule Inhibitors ◽  
Dynamics Simulation

The blockade of the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway plays a critical role in cancer immunotherapy by reducing the immune escape. Five monoclonal antibodies that antagonized PD-1/PD-L1 interaction have been approved by the Food and Drug Administration (FDA) and marketed as immunotherapy for cancer treatment. However, some weaknesses of antibodies, such as high cost, low stability, poor amenability for oral administration, and immunogenicity, should not be overlooked. To overcome these disadvantages, small-molecule inhibitors targeting PD-L1 were developed. In the present work, we applied in silico and in vitro approaches to develop short peptides targeting PD-1 as chemical probes for the inhibition of PD-1–PD-L1 interaction. We first predicted the potential binding pocket on PD-1/PD-L1 protein–protein interface (PPI). Sequentially, we carried out virtual screening against our in-house peptide library to identify potential ligands. WANG-003, WANG-004, and WANG-005, three of our in-house peptides, were predicted to bind to PD-1 with promising docking scores. Next, we conducted molecular docking and molecular dynamics (MD) simulation for the further analysis of interactions between our peptides and PD-1. Finally, we evaluated the affinity between peptides and PD-1 by surface plasmon resonance (SPR) binding technology. The present study provides a new perspective for the development of PD-1 inhibitors that disrupt PD-1–PD-L1 interactions. These promising peptides have the potential to be utilized as a novel chemical probe for further studies, as well as providing a foundation for further designs of potent small-molecule inhibitors targeting PD-1.

Inhibitory activity of bovine lactoferrin against echovirus induced programmed cell death in vitro

2005 ◽  
Vol 25 (5) ◽  
pp. 433-438 ◽  
Author(s):  
Antonella Tinari ◽  
Agostina Pietrantoni ◽  
Maria Grazia Ammendolia ◽  
Piera Valenti ◽  
Fabiana Superti
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Inhibitory Activity ◽  
Bovine Lactoferrin

scholarly journals Molecular Mechanism of Food-Derived Polyphenols on PD-L1 Dimerization: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 22 (20) ◽  
pp. 10924
Author(s):  
Yan Guo ◽  
Jianhuai Liang ◽  
Boping Liu ◽  
Yulong Jin
Keyword(s):  
Molecular Dynamics ◽  
Cell Death ◽  
Free Energy ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Molecular Mechanism ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Binding Free Energy ◽  
Dynamics Simulation

In cancer immunotherapy, an emerging approach is to block the interactions of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) using small-molecule inhibitors. The food-derived polyphenols curcumin (CC), res (RSV) and epigallocatechin gallate (EGCG) have anticancer immunologic functions, which, recently, have been proposed to act via the downregulation of PD-L1 expression. However, it remains unclear whether they can directly target PD-L1 dimerization and, thus, interrupt the PD-1/PD-L1 pathway. To elucidate the molecular mechanism of such compounds on PD-L1 dimerization, molecular docking and nanosecond molecular dynamics simulations were performed. Binding free energy calculations show that the affinities of CC, RSV and EGCG to the PD-L1 dimer follow a trend of CC > RSV > EGCG. Hence, CC is the most effective inhibitor of the PD-1/PD-L1 pathway. Analysis on contact numbers, nonbonded interactions and residue energy decomposition indicate that such compounds mainly interact with the C-, F- and G-sheet fragments of the PD-L1 dimer, which are involved in interactions with PD-1. More importantly, nonpolar interactions between these compounds and the key residues Ile54, Tyr56, Met115, Ala121 and Tyr123 play a dominant role in binding. Free energy landscape and secondary structure analyses further demonstrate that such compounds can stably interact with the binding domain of the PD-L1 dimer. The results provide evidence that CC, RSV and EGCG can inhibit PD-1/PD-L1 interactions by directly targeting PD-L1 dimerization. This provides a novel approach to discovering food-derived small-molecule inhibitors of the PD-1/PD-L1 pathway with potential applications in cancer immunotherapy.

scholarly journals Discovery of Novel Small-Molecule Inhibitors of PD-1/PD-L1 Interaction via Structural Simplification Strategy

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3347
Author(s):  
Hongbo Zhang ◽  
Yu Xia ◽  
Chunqiu Yu ◽  
Huijie Du ◽  
Jinchang Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Life Time ◽  
Production Costs ◽  
Dependent Manner ◽  
Starting Point ◽  
Cell Inhibition ◽  
Structural Simplification

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC50 = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (KD = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.

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