Chemical Chaperone and Inhibitor Discovery: Potential Treatments for Protein Conformational Diseases

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 fibrosis and α1-antitrypsin deficiency. 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.

Marine fish may be biochemically constrained from inhabiting the deepest ocean depths

“…In particular, TMAO is a potent protein stabilizer that is able to counteract the effects of destabilizers, including temperature and urea, and to enhance protein folding in general (18)(19)(20). The latter property has led to the term "chemical chaperone" for TMAO and related stabilizers, with potential medical and biotechnological applications (21). Importantly, TMAO (but not glycine or other common osmolytes) has been found to Significance Fish appear to be absent from the ocean's greatest depths, the trenches from 8,400-11,000 m. The reason is unknown, but hydrostatic pressure is suspected.…”

Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease

“…Small molecule chaperones are low molecular weight compounds that exhibit their own chaperone function by enhancing protein stabilization and folding processes and by antagonizing protein aggregation [ 10 , 85 ]. These compounds are distinct from molecular chaperones in that they are neither proteins nor components of the cell's primary response mechanism to proteotoxic stress.…”

“…Chemical chaperones are classified as either osmolytes or hydrophobic compounds and typically promote protein folding nonspecifically by creating a chemical environment that encourages proteins to acquire the proper conformation [ 10 ]. In contrast, pharmacological chaperones bind directly to their target protein(s) to modulate its conformation and stability [ 10 , 85 ].…”

Target- and Mechanism-Based Therapeutics for Neurodegenerative Diseases: Strength in Numbers

“…The use of chemical chaperones, small molecules having the ability to stabilize unfolded monomer conformations and/or to destabilize misfolded oligomers, has been widely explored. 303, 304 An alternative approach involves the use of metal chelators, compounds that sequester physiological metal ions, and in so doing, block protein aggregation. Aβ, for example, shows ready binding to metals such as Zn 2+ and Cu 2+ , which induce nucleation and the formation of aggregate plaques.…”