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bioRxiv · 10.1101/2024.07.13.603377

Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation

Chatterjee, B.·Alam, M.·Chakravorty, A.·Lacy, S.·Rech, J.·Brooks, C. L.·Arvan, P.·Truttmann, M.
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Abstract

The AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional 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 to 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 efficiently inhibit pathogenic FICD variants and improve proinsulin processing in {beta} cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.

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Chatterjee, B., Alam, M., Chakravorty, A., Lacy, S., Rech, J., Brooks, C. L., Arvan, P., Truttmann, M.. 2024-07-16. Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation. https://doi.org/10.1101/2024.07.13.603377

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