Abnormal protein aggregation is responsible for a variety of human disorders, including Alzheimer's disease, Creutzfeldt–Jakob disease, systemic amyloidosis, and α1-antitrypsin deficiency (AATD). These diseases are collectively termed conformational diseases and many of them are lethal and have no cure to date. The pathogenesis of these clinical conditions shares a common mechanism of disease, i.e., formation of large protein tangles through intermolecular linkages, cross-β-sheets in particular. These tenacious aggregates are difficult to eradicate and accumulate in cells or tissues over affected individual's lifetime, which eventually leads to devastating consequences. The chronic process is commonly underdiagnosed at an early stage and the prevalence of conformational disease is higher than generally realized. AATD is a typical conformational disease causing both lung and liver disorders, and the World Health Organization (WHO) has highlighted the healthcare problem in 1996. The mechanism of AATD has been unraveled and it serves as an excellent model for the study of conformational disease. Point mutations render α1-antitrypsin susceptible to self-aggregation and form stacked β-sheets, which is the hallmark of AATD and other conformational diseases. The key to attenuating these diseases is searching for small molecules capable of preventing the formation of large aggregates and dissociating the pre-existing oligomers. To this end, a chemical approach has been developed to tackle the biological problem.
