Next Article in Journal
Stealth Magnetoliposomes Based on Calcium-Substituted Magnesium Ferrite Nanoparticles for Curcumin Transport and Release
Previous Article in Journal
KRAB-Induced Heterochromatin Effectively Silences PLOD2 Gene Expression in Somatic Cells and Is Resilient to TGFβ1 Activation
Previous Article in Special Issue
Accurate Representation of Protein-Ligand Structural Diversity in the Protein Data Bank (PDB)
Open AccessArticle

Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions

1
Nano Medical Engineering Laboratory, RIKEN Cluster of Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
2
Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan
3
Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3639; https://doi.org/10.3390/ijms21103639
Received: 7 April 2020 / Revised: 14 May 2020 / Accepted: 17 May 2020 / Published: 21 May 2020
Cancer immunotherapy has been revolutionized by the development of monoclonal antibodies (mAbs) that inhibit interactions between immune checkpoint molecules, such as programmed cell-death 1 (PD-1), and its ligand PD-L1. However, mAb-based drugs have some drawbacks, including poor tumor penetration and high production costs, which could potentially be overcome by small molecule drugs. BMS-8, one of the potent small molecule drugs, induces homodimerization of PD-L1, thereby inhibiting its binding to PD-1. Our assay system revealed that BMS-8 inhibited the PD-1/PD-L1 interaction with IC50 of 7.2 μM. To improve the IC50 value, we designed and synthesized a small molecule based on the molecular structure of BMS-8 by in silico simulation. As a result, we successfully prepared a biphenyl-conjugated bromotyrosine (X) with IC50 of 1.5 μM, which was about five times improved from BMS-8. We further prepared amino acid conjugates of X (amino-X), to elucidate a correlation between the docking modes of the amino-Xs and IC50 values. The results suggested that the displacement of amino-Xs from the BMS-8 in the pocket of PD-L1 homodimer correlated with IC50 values. This observation provides us a further insight how to derivatize X for better inhibitory effect. View Full-Text
Keywords: PD-1/PD-L1; immune checkpoint inhibitors; biphenyl-conjugated bromotyrosine; amino acid conjugation; amino-X; in silico simulation; IC50 PD-1/PD-L1; immune checkpoint inhibitors; biphenyl-conjugated bromotyrosine; amino acid conjugation; amino-X; in silico simulation; IC50
Show Figures

Graphical abstract

MDPI and ACS Style

Kim, E.-H.; Kawamoto, M.; Dharmatti, R.; Kobatake, E.; Ito, Y.; Miyatake, H. Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions. Int. J. Mol. Sci. 2020, 21, 3639.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop