Rational design of potent Peptide Inhibitors of the PD-1:PD-L1 interaction for Cancer Immunotherapy Huawu Yin 1 , Xiuman Zhou 2 , Yen-Hua Huang 1 , Gordon J. King 1 ,Brett M. Collins 1 , Yanfeng Gao 2 , David J. Craik 1 , Conan K. Wang 1 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia 2 School of Life Sciences, Zhengzhou University, China Peptides, occupy a size gap in the drug modality landscape and have potential to be developed into novel inhibitors of immune checkpoint protein-protein interactions, which are challenging to target. Here, I will present an exemplar case of mimicry, in which PD:L1 targeted peptides are designed via mimicking the interface of an affinity-optimized parent protein rather than the native PD-1. This work resulted in a peptide mimetic MOPD-1 that showed strong bioactivity in both in vitro and in vivo 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. MOPD-1 was extremely stable in human serum and inhibited tumor growth in vivo, suggesting it has potential for use in cancer immunotherapy. The design approach used here could have broad applications in drug design. References 1. Huawu Yin,Xiuman Zhou,Yen-Hua Huang, Gordon J. King, Brett M. Collins,Yanfeng Gao, David J. Craik, Conan K. Wang.J. Am. Chem. Soc. 2021, 143, 18536-18547.
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