Small-Molecule FICD Inhibitors Suppress Endogenous and Pathologic FICD-Mediated Protein AMPylation.

IF 3.5 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Biology Pub Date : 2025-04-18 Epub Date: 2025-03-04 DOI:10.1021/acschembio.4c00847

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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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.

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小分子FICD抑制剂抑制内源性和病理性FICD介导的蛋白amppyation。

AMP转移酶（FICD）是一种新兴的靶向内质网（ER）微调应激信号的药物。FICD是一种双功能酶，可催化内质网伴侣BiP/GRP78的AMP加成（AMPylation）和去除（deAMPylation）。尽管越来越多的证据表明过度的BiP/GRP78 ampyylation与人类疾病有关，但抑制致病性FICD变体的小分子仍然缺乏。通过体外高通量筛选，我们鉴定出两种小分子FICD抑制剂C22和C73。在完整细胞中，这两种分子均显著抑制ficd介导的BiP/GRP78 ampyation，而仅微弱抑制BiP/GRP78 deampyation。C22和C73还能抑制致病性FICD变异并改善β细胞中的胰岛素原加工。我们的研究鉴定并验证了FICD抑制剂，强调了一种针对病理性蛋白ampyation的新治疗途径。

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来源期刊

ACS Chemical Biology 生物-生化与分子生物学

CiteScore

7.50

自引率

5.00%

发文量

353

审稿时长

3.3 months

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.