Work

Synthesis of Chirally Chimeric Protein Nanoparticle Vaccines via Mirror‐Image Spy Chemistry

Year: 2025

Type: article

Abstract: Mirror‐image proteins and nucleic acids exhibit remarkable biostability and bioorthogonality, offering a promising strategy to enhance the longevity of biological therapeutics. Here, we present a modular approach for constructing complex protein architectures that integrate both natural‐chirality ( L ‐) and mirror‐image ( D ‐) motifs. Key to this strategy is the development of D ‐SpyStapler—a chemically synthesized, chirally inverted ligase that enables the efficient conjugation of D ‐SpyTag and D ‐BDTag. By exploiting the achirality of glycine (Gly), we used L ‐sortase to covalently link D ‐peptides (e.g., SpyTag or BDTag, bearing an N‐terminal poly‐Gly motif) to L ‐proteins (e.g., GFP, VLP‐forming Mi3, or antigens) containing a C‐terminal LPXTG sorting signal. The resulting D ‐SpyTagged and D ‐BDTagged proteins were further assembled via D ‐SpyStapler. This method enabled the construction of chirally chimeric VLP vaccines displaying antigens derived from malaria parasites and coronaviruses in various forms—recombinant proteins or synthetic peptides—providing significant flexibility and modularity for vaccine design. The resulting chirally hybrid vaccines exhibited enhanced proteolytic resistance in vitro and elicited potent immune responses in vivo. This study provides a versatile platform for developing long‐acting therapeutics and vaccines.

Source: Angewandte Chemie

DOI: 10.1002/ange.202509419

Authors: Songzi Kou, Chenbo Sun, Weitao Chen, Hanyu Gao, Fei Sun

Institutions: Shenzhen Bay Laboratory, Hong Kong University of Science and Technology

Language: English

Topic: Biochemical and Structural Characterization

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,790