Most neurodegenerative diseases are proteopathies. Alleviating ER stress is a promising approach for treating a range of diseases. Heren researchers aimed to identify a potent chemical chaperone through High-Throughput Screening of a small molecule chemical library.
The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. For example Tudca (see AMX00035 trial) has some efficiency in this area. Tudca is a chemical chaperone.
Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Scientists have identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen.
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) is called ER stress. The cell has an adaptive system against ER stress called the unfolded protein response (UPR), which is the coordinated transcriptional upregulation of ER chaperones and folding enzymes that prevents the aggregation of unfolded and incompletely folded protein.
To overcome ER stress-related diseases, the following two pharmacological strategies can be applied: the modulation of ER protein folding environments (by UPR modulators) and a reduction in the accumulation of unfolded or misfolded ER proteins (by chemical chaperones).
In contrast, several chemical chaperones that have shown therapeutic benefits in mouse disease models have also been developed. 4-Phenylbutyrate (4PBA) and taurourso-deoxycholic acid (TUDCA) have been reported to function as chemical chaperones and have shown therapeutic benefits for a wide variety of diseases, such as diabetes, ALS and Alzheimer's disease.
Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, their data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.