Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics

Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to the soluble amyloid-β protofibrils, all the treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling to find a breakthrough in AD therapeutic medicine, which is partially attributable to lack in understanding of the structural information associated with the intrinsically disordered proteins and amyloids. One of the major challenges in this area of research is to understand the structural diversity of intrinsically disordered proteins under in vitro conditions. Therefore, in this review, we have summarized the in vitro applications of biophysical methods, which are aimed to shed some light on the heterogeneity, pathogenicity, structures and mechanisms of the intrinsically disordered protein aggregates associated with proteinopathies including AD. This review will also rationalize some of the strategies in modulating disease-relevant pathogenic protein entities by small molecules using structural biology approaches and biophysical characterization. We have also highlighted tools and techniques to simulate the in vivo conditions for native and cytotoxic tau/amyloids assemblies, urge new chemical approaches to replicate tau/amyloids assemblies similar to those in vivo conditions, in addition to designing novel potential drugs.