Discovery of hPRDX5-based peptide inhibitors blocking PD-1/PD-L1 interaction through in silico proteolysis and rational design
The human peroxiredoxin-5 (hPRDX5) is a member of the family of antioxidant enzymes, which could resist immunosuppression by promoting immune organs development, lymphocyte proliferation and up-regulation of the levels of serum cytokines. However, being a recombinant protein, the hPRDX5 exhibits some problems including the high production cost and bad tissue penetration. Compared to macromolecular therapeutic agents, synthetic peptides have several advantages as drug candidates, such as lower manufacturing costs, reduced immunogenicity, and better organ or tumor penetration. The purpose of this research was to design the novel peptides come from hPRDX5 that can block the interaction of PD-1 and PD-L1.
Herein in this work, we firstly confirmed the inhibitory activity of hPRDX5 on the binding of PD-L1 to PD-1 based on the previous observation, subsequently, in silico proteolysis and rational design (such as alanine scanning mutagenesis and truncation) were used to automate the design of new peptides derived from hPRDX5 with anti-tumour activity.
We found that the most potent peptide could block the PD-1/PD-L1 interaction effectively with an IC50 of 0.646 μM, and could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Moreover, experiments with tumor-bearing mice models showed that the peptide IMB-P6-10 could effectively inhibit tumor growth and showed extraordinary low acute toxicity in vivo.
The peptides described in this paper may provide novel low-molecular-weight drug candidates for cancer immunotherapy.
KeywordsPeptide inhibitor Human peroxiredoxin-5 Immunotherapy Rational design Protein–protein interactions (PPIs)
We thank Dr. Guangteng Wu (ArNuXon Pharm-Sci Co., Ltd., Beijing) for the manuscript revision.
This work was supported by the CAMS Innovation Fund for Medical Sciences (Grants 2016-I2 M-3-022), National Natural Science Foundation of China (Grants 81761128016 and 8187131584) and National Mega-project for Innovative Drugs (Grants 2018ZX09711001-006-001 and 2018ZX09711001-007-003).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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