Design of polysulfobetaine derivatives for enhanced inhibition of protein aggregation

Abstract

Protein aggregation and misfolding are implicated in neurodegerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease. The inhibition of these processes by polymers is a promising therapeutic approach but currently an underexplored area of research. In this study, we synthesised and evaluated new polysulfobetaine (PSPB) derivatives for protein stabilisation under thermal stress. These PSPB derivatives effectively stabilised various proteins, including lysozyme, insulin, and lactate dehydrogenase, indicating their broad-spectrum utility. The enhanced stabilisation was due to the introduction of a hydrophobic moiety into the PSPB structure, suggesting the vital role of hydrophobic interactions in preventing protein aggregation. The incorporation of trehalose also improved protein stability, likely due to a synergistic effect. Additionally, transforming the PSPB structure into a star-shaped architecture increased the surface area and functional sites. This enhanced its interaction with proteins, which effectively hindered aggregation. These findings underscore the potential of PSPB derivatives as biopharmaceutical stabilisers for the treatment of protein-aggregation-related neurodegenerative diseases.