Aberrant protein misfolding is associated with a myriad of human diseases, including neurodegenerative diseases such as Alzheimer’s as well as systemic amyloid diseases such as light chain amyloidosis. In this family of disorders, misfolded proteins can bypass or overwhelm cellular quality control mechanisms to aggregate and cause gain-of-function toxicity and cell death. A general approach toward the treatment of these disorders could be to activate appropriate stress-responsive signaling pathways that operate in specific cellular compartments, such as the Unfolded Protein Response in the Endoplasmic Reticulum or the Heat Shock Response in the cytosol. The discovery of a new lead series of small-molecule activators of the ATF6 arm of the Unfolded Protein Response has allowed for this therapeutic direction to be explored as a general treatment for systemic amyloid diseases. Furthermore, the design and synthesis of releasable small-molecule heat shock response activators have the potential to apply this approach as a strategy to combat neurodegenerative disease.

Chemical and biological approaches for the treatment of protein misfolding and aggregation diseases

251st National Meeting (2016)

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