Mitigating Uricase Immunogenicity through Zwitterionic Peptide Fusion for Enhanced Gout Therapy

Uricase is a promising protein drug for treating gout, but its therapeutic efficacy is significantly limited by its high immunogenicity. In this study, we successfully mitigated the immunogenicity of uricase by fusing zwitterionic peptides (repeated VPKEG sequences) with varying lengths through synthetic biology. The results show that longer zwitterionic peptides can more efficiently improve the enzymatic activity, enhance the substrate affinity, prolong the blood circulation time, and reduce the antibody response. This is likely due to the longer zwitterionic peptides providing a more extensive protective hydration layer, which can shield the immunogenic sites of uricase. As a result, U-(VPKEG)60, the uricase with the longest zwitterionic peptide, significantly enhances therapeutic effects for rat gout models. Moreover, it also exhibits excellent biocompatibility with no hemolysis and negligible cytotoxicity to liver, heart, and kidney functions. Our findings provide new insights into the development of low-immunogenicity uricase through synthetic biology.