posted on 2021-10-18, 13:07authored byHuawu Yin, Xiuman Zhou, Yen-Hua Huang, Gordon J. King, Brett M. Collins, Yanfeng Gao, David J. Craik, Conan K. Wang
Peptides have potential to be developed
into immune checkpoint
inhibitors, but the target interfaces are difficult to inhibit. Here,
we explored an approach to mimic the binding surface of PD-1 to design
inhibitors. Mimicking native PD-1 resulted in a mimetic with no activity.
However, mimicking an affinity-optimized PD-1 resulted in the peptide
mimetic MOPD-1 that displayed nanomolar affinity to PD-L1 and could
inhibit PD-1:PD-L1 interactions in both protein- and cell-based assays.
Mutagenesis and structural characterization using NMR spectroscopy
and X-ray crystallography revealed that binding residues from the
high affinity PD-1 are crucial for the bioactivity of MOPD-1. Furthermore,
MOPD-1 was extremely stable in human serum and inhibited tumor growth in vivo, suggesting it has potential for use in cancer immunotherapy.
The successful design of an inhibitor of PD-1:PD-L1 using the mimicry
approach described herein illustrates the value of placing greater
emphasis on optimizing the target interface before inhibitor design
and is an approach that could have broader utility for the design
of peptide inhibitors for other complex protein–protein interactions.