Dissecting Uricase Immunogenicity: Unveiling the Role of Quaternary Epitopes through In Silico Analysis

Quaternary Epitope Insights in Uricase Immunogenicity

Abstract

Background: Protein-based therapeutics offer remarkable precision and effectiveness, yet their immunogenic potential remains a significant challenge. Uricase, an enzyme used to treat hyperuricemia, is no exception, often eliciting immune responses due to its non-human origins and repeated administration requirements. Understanding the immunogenic mechanisms at play is crucial for enhancing therapeutic efficacy. Materials and Methods: This in silico study investigates the immunogenic landscape of uricase, focusing on the identification of linear, conformational, and the underexplored quaternary epitopes. Using a comprehensive approach, we analyzed multiple uricase variants through structural alignments, epitope prediction algorithms, and network-based residue interaction models. Predictive tools, including BepiPred, DiscoTope, and SEMA, were employed to identify epitope regions, with a novel focus on quaternary epitopes formed by inter-chain interactions. Results: Our analysis reveals conserved structural motifs across uricase variants, with linear and conformational epitopes localized in similar regions. The groundbreaking identification of quaternary epitopes—epitopes formed through interactions between protein chains—provides a novel insight into uricase immunogenicity. These epitopes, located in structurally prominent regions, likely play a critical role in the immune response to uricase. Conclusions: This study marks a significant advance in understanding uricase immunogenicity, introducing quaternary epitopes as pivotal factors in immune recognition. The findings open new avenues for designing uricase variants with reduced immunogenicity, offering potential improvements in therapeutic strategies for hyperuricemia management.