Development of Mirror-Image Protein Drugs： Advances in Chemical Synthesis， Mirror-Image Phage Display， and Computational Design

Ren Yuxiang; Han Dongyang; Shi Weiwei

doi:10.7536/PC20250315

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Prog Chem ›› 2025, Vol. 37 ›› Issue (9) : 1261-1273. DOI: 10.7536/PC20250315

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Development of Mirror-Image Protein Drugs： Advances in Chemical Synthesis， Mirror-Image Phage Display， and Computational Design

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Abstract

Mirror-image peptides and proteins composed entirely of D-amino acids have emerged as promising therapeutic candidates owing to their resistance to proteolysis and reduced immunogenicity. Mirror-image phage display （MIPD） is currently the main experimental technique for identifying mirror-image peptide ligands targeting disease-related proteins. However， the success of MIPD critically depends on synthetic mirror-image target proteins， which cannot be produced by traditional recombinant methods due to the intrinsic chirality of biological systems. Recent advances in chemical protein synthesis， such as enzyme-cleavable solubilizing tags， backbone-installed split intein-assisted ligation， and removable glycosylation modification-assisted folding strategies， have effectively addressed key challenges in preparing these complex mirror-image proteins. In addition， computational approaches， exemplified by AI-driven protein design， have become powerful complementary tools， accelerating the discovery and optimization of mirror-image protein drug candidates. Although mirror-image protein drugs have not yet reached clinical use， ongoing innovations in chemical synthesis and ligand screening methods are steadily advancing their therapeutic potential toward clinical translation.

Contents

1 Introduction

2 Mirror-image phage display

3 Chemical protein synthesis

3.1 Solid-phase peptide synthesis

3.2 Native chemical ligation

3.3 Peptide hydrazide ligation

3.4 Multiple-segment ligation

3.5 The ligation-desulfurization strategy

3.6 Solubilizing tags for hydrophobic segment

3.7 Chemoenzymatic D-peptide ligation

3.8 The folding of D-protein

4 Applications of mirror-image phage display

5 Computationally assisted discovery of mirror-image protein drugs

6 Conclusion and outlook

Key words

mirror-image protein / chemical protein synthesis / mirror-image phage display / protein de novo design

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Ren Yuxiang , Han Dongyang , Shi Weiwei. Development of Mirror-Image Protein Drugs： Advances in Chemical Synthesis， Mirror-Image Phage Display， and Computational Design[J]. Progress in Chemistry. 2025, 37(9): 1261-1273 https://doi.org/10.7536/PC20250315

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Funding

The National Natural Science Foundation of China(22307061)

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