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Trends Mol Med. 2005 Aug;11(8):347-50.

A new pharmacology--drugging stressed folding pathways.

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  • 1Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd, MB-6, La Jolla, CA 92037, USA.


Folding in the endoplasmic reticulum (ER) must couple protein-synthesis pathways operating outside of the compartment with ER-assisted folding (ERAF) pathways in the lumen. Chaperone-mediated folding imbalances that are associated with numerous misfolding diseases, including diabetes, trigger the unfolded-protein response (UPR), using both transcriptional and translational pathways to correct the problem. Recent work suggests that small-molecule inhibitors could be useful to help rebalance protein synthesis with ERAF pathways through the ribosomal initiating factor eIF2alpha. Reprogramming stress pathways with drugs provides a potential new approach for balancing ER-protein load with cellular-folding capacity, thus correcting disease.

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