Conformational inhibitors of protein aggregation

Amyloidoses are fatal conditions associated with the aggregation of proteins into amyloid fibrils that deposit systemically and/or locally. Possibly because the causal mechanism of protein aggregation and deposition is not fully understood, this group of diseases remains uncurable. Advances in structural biology, such as the use of nuclear magnetic resonance and cryo-electron microscopy, have enabled the study of the structures and the conformational nature of the proteins whose aggregation is associated with the underlying pathogenesis of amyloidosis. As a result, the last years of research have translated into the development of directed therapeutic strategies that target the specific conformations of precursors, fibrils, and intermediary species. Current efforts include the use of small molecules, peptides, and antibodies. This review summarizes the recent progress in developing strategies that target specific protein conformations for the treatment of amyloidoses. The amyloid aggregation cascade in localized and systemic deposition starts with the unfolding and/or misfolding of the precursor protein, which self-aggregates into elongated structures known as amyloid fibrils. The different species that evolve from this process adopt structural features that can be used to specifically target them to halt the aggregation cascade. In this review, we summarize the latest efforts towards the development of conformational inhibitors, including small compounds, peptides and miniproteins, and antibodies. PDB code of the intermediate species is 3SG0. [Display omitted] •Here we review the latest advancements in protein aggregation inhibitors.•Those can be small molecules, peptides, miniproteins, antibodies, and derivatives.•They specifically target precursors proteins, intermediate, or mature aggregates.