Si et al. propose an innovative vaccine strategy that utilizes PROTAC technology to create artificially attenuated influenza strains, a strategy that promises to overcome the limitations of traditional vaccine preparation methods. By linking the proteasome-targeting domain (PTD) to a specific protein of the influenza virus, and using the host cell’s ubiquitin-proteasome system, they successfully degraded the viral protein, significantly reducing the virus’s ability to replicate.
PTD, a heptapeptide sequence (ALAPYIP) recognized by VHL E3 ubiquitin ligase, is linked to the viral protein via a TEV protease cleavage site (ENLYFQG), allowing the PTD to be conditionally excised in cells expressing TEV protease, avoiding degradation of the viral protein. This mechanism ensures that in certain cell lines, the virus replicates normally, while in others it is severely weakened, and the resulting attenuated virus can be used for vaccine production.
The research team performed PTD labeling tests on eight key proteins of influenza A virus and found that the M1 protein-labeled virus (M1-PTD) was more than 20,000 times less able to replicate in ordinary cells, but still replicated effectively in TEV protease-expressing cells. The M1-PTD virus elicits a significant immune response in both mouse and ferret models, including high levels of hemagglutinin inhibiting antibodies and neutralizing antibodies, as well as an enhanced T cell immune response.
The advantages of PROTAC virus as a vaccine candidate are that it can ensure safety while maintaining high immunogenicity, and activate the proteasome degradation pathway by degrading viral peptides, triggering a more effective immune response. Compared to traditional vaccine preparation techniques, PROTAC technology not only improves safety, but also reduces the loss of efficacy and productivity, and may reduce immune escape problems caused by rapid virus evolution. Therefore, PROTAC technology has become an important option for the production of safer and more effective vaccines. This breakthrough approach opens a new path to developing safer and more effective vaccines.
