Background: We have seen how disruptive modalities in drug design such as mRNA-based vaccines have led to a quantum leap in medicine. Here, we focus on a next-generation modality for cancer immunotherapy - miniature proteins called peptides. Important translational benefits of peptides compared to monoclonal antibodies include lower cost of production and increased tumour penetration. However, design of peptidic inhibitors of immune checkpoints has been challenging.
Aim: We demonstrate a new approach in which we first visualise the checkpoint interactions for PD-1/PD-L1, and then identify a downsized analogue with shape-mimicking properties.
Results: Our mimetic 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 the shape of our mimetic is crucial for the bioactivity of MOPD-1. Furthermore, our mimetic was extremely stable in human serum and inhibited colorectal tumor growth in vivo, suggesting it has potential for use in cancer immunotherapy.
Significance: The successful design of an inhibitor of PD-1:PD-L1 creates opportunities to explore its application for treatment of other cancers and use of our approach to target new checkpoint inhibitors, for which collaborations are currently being sought.
Reference: Yin H, Zhou X, Huang YH, King GJ, Collins BM, Gao Y, Craik DJ, Wang CK (2020) Rational Design of Potent Peptide Inhibitors of the PD-1:PD-L1 Interactions for Cancer Immunotherapy. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.1c08132