A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency
Salima Daou, Manisha Talukdar, Jinle Tang, Beihua Dong, Shuvojit Banerjee, Yize Li, Nicole M. Duffy, Abiodun A. Ogunjimi, Christina Gaughan, Babal K. Jha, Gerald Gish, Nicolas Tavernier, Daniel Y.L. Mao, Susan R. Weiss, Hao Huang, Robert H. Silverman, Frank Sicheri
Abstract
is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential.