Bhaskar K Chatterjee, Maroof Alam, Arghya Chakravorty, Shannon M Lacy, William Giblin, Jason Rech, Charles L Brooks, Peter Arvan, Matthias C Truttmann
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引用次数: 0
Abstract
The AMP transferase, FICD, is an emerging drug target fine-tuning stress signaling in the endoplasmic reticulum (ER). FICD is a bifunctional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER-resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules that inhibit pathogenic FICD variants are lacking. Using an in vitro high-throughput screen, we identify two small-molecule FICD inhibitors, C22 and C73. Both molecules significantly inhibit FICD-mediated BiP/GRP78 AMPylation in intact cells while only weakly inhibiting BiP/GRP78 deAMPylation. C22 and C73 also inhibit pathogenic FICD variants and improve proinsulin processing in β cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.
期刊介绍：
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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