Inhibition of FicD-mediated AMPylation and deAMPylation by Isoprenoid Diphosphates
FicD regulates UPR signaling in metazoans by fine-tuning BiP chaperone capacity. Therefore, targeting FicD activity may be a tractable method of altering UPR signaling for therapeutic benefit. We identify geranyl- and farnesyl-pyrophosphate as specific FicD inhibitors. Notably, these small molecules differentially inhibit disease-causing variants of FicD. A structure of farnesyl-pyrophosphate bound to the FicD active site helps explain the differential inhibition of pathogenic variants and provides insight into interactions that can be differentially exploited for modifying FicD activity. Their composition provides a novel chemical foundation for future drug development efforts targeting FicD activity.
Authors
- Aubrie Blevins (ORCID: https://orcid.org/0000-0002-4546-7267)
- Wei Peng (ORCID: https://orcid.org/0000-0002-3325-4002)
- Lisa N. Kinch (ORCID: https://orcid.org/0000-0003-3041-2615)
- Kevin G. Hicks (ORCID: https://orcid.org/0000-0001-5067-7608)
- Kim Orth (ORCID: https://orcid.org/0000-0002-0678-7620)
- Jared Rutter (ORCID: https://orcid.org/0000-0002-2710-9765)
- Ana Paredes (ORCID: https://orcid.org/0000-0003-3119-8788)
- Amanda K. Casey (ORCID: https://orcid.org/0000-0002-5829-748X)
- Zihan Monshad
- Christina Volz
Institutions
- University of Utah (US)
- Southwestern Medical Center (US)
- University of Utah Health Care (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-08
- DOI
- https://doi.org/10.64898/2025.12.08.693056
- Primary Topic
- Legionella and Acanthamoeba research
- Type
- article
- Field-Weighted Citation Impact
- 0.00