Jian-Hua Zhao¹, Hsuan-Liang Liu^1,2, Hsin-Yi Lin^1,2, Chih-Hung Huang^1,2, Hsu-Wei Fang^1,2, Shiao-Shing Chen³, Yih Ho⁴, Wei-Bor Tsai⁵ and Wen-Yih Chen⁶

¹Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei 10608. ²Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, Taiwan 10608. ³Institute of Environmental Engineering and Management, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, Taiwan 10608. ⁴School of Pharmacy, Taipei Medical University, 250 Wu-Hsing St., Taipei, Taiwan 110. ⁵Department of Chemical Engineering, National Taiwan University, 1 Sec. 4 Roosevelt Rd., Taipei, Taiwan 106. ⁶Department of Chemical and Materials Engineering, National Central University, 300 Jhongda Rd., Jhongli City, Taoyuan County, Taiwan 32001.

Abstract: Protein misfolding and aggregation cause a large number of neurodegenerative diseases in humans due to (i) gain of function as observed in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and Prion’s disease or (ii) loss of function as observed in cystic fi brosis and α1-antitrypsin defi ciency. These misfolded proteins could either lead to the formation of harmful amyloids that become toxic for the cells or to be recognized and prematurely degraded by the protein quality control system. An increasing number of studies has indicated that some low-molecular-weight compounds named as chemical chaperones can reverse the mislocalization and/or aggregation of proteins associated with human conformational diseases. These small molecules are thought to non-selectively stabilize proteins and facilitate their folding. In this review, we summarize the probable mechanisms of protein conformational diseases in humans and the use of chemical chaperones and inhibitors as potential therapeutic agents against these diseases. Furthermore, recent advanced experimental and theoretical approaches underlying the detailed mechanisms of protein conformational changes and current structure-based drug designs towards protein conformational diseases are also discussed. It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.