Amyloidoses are a clinically diverse group of disorders characterized by the deposition of amyloid fibrils. Amyloid fibrils share a typical cross β structure that leads to a distinct X-ray diffraction pattern, which comprises a 4.75 Å reflection corresponding to the spacing between β strands and a 10 Å reflection corresponding to the distance between β sheets [1]. Amyloid fibrils can deposit locally or systemically, and the distinction between the two is made based on whether the production site of the precursor protein is the same as the deposition site [2]. In systemic amyloidosis, the production site of the precursor protein is anatomically distant from its deposition site. In localized amyloidosis, the precursor protein is synthesized at its site of deposition [3]. Currently, 20 proteins have been implicated in systemic amyloidoses, and 27 in localized amyloidosis [2]. Currently, all amyloidoses remain incurable.

In recent years, there has been an unprecedented advancement in the development of protein aggregation inhibitors, some of which are now marketed for the treatment of amyloidosis. The first-ever approved protein aggregation inhibitor for the treatment of amyloidosis was tafamidis, a small molecule that targets the native structure of the amyloid precursor transthyretin [4]. Since then, many other molecules have been designed and tested, including small molecules, peptides, miniproteins, antibodies, and derivatives. These were designed to either target the precursor amyloid proteins, the matured amyloid fibrils, or intermediate species. Here, we review current strategies for developing conformation-specific aggregation inhibitors with emphasis on promising recent efforts under different stages of preclinical and clinical testing. Figure 1 provides an overview of the topics discussed here. Table 1 offers a list of conformational strategies to prevent, inhibit, and/or clear protein aggregation that are currently being tested in clinical trials; some of these are discussed in this review.