Back to Search
Start Over
A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Oct 06; Vol. 117 (40), pp. 24802-24812. Date of Electronic Publication: 2020 Sep 21. - Publication Year :
- 2020
-
Abstract
- The oligoadenylate synthetase (OAS)-RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 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.<br />Competing Interests: The authors declare no competing interest.<br /> (Copyright © 2020 the Author(s). Published by PNAS.)
- Subjects :
- 2',5'-Oligoadenylate Synthetase genetics
2',5'-Oligoadenylate Synthetase metabolism
Adenine Nucleotides metabolism
Adenosine Deaminase genetics
Autoimmune Diseases of the Nervous System genetics
Autoimmune Diseases of the Nervous System physiopathology
Cell Death drug effects
Endoribonucleases genetics
Endoribonucleases metabolism
Enzyme Inhibitors chemistry
Humans
Nervous System Malformations genetics
Nervous System Malformations physiopathology
Oligoribonucleotides metabolism
Phenol chemistry
RNA-Binding Proteins genetics
Adenosine Deaminase deficiency
Autoimmune Diseases of the Nervous System enzymology
Endoribonucleases antagonists & inhibitors
Enzyme Inhibitors pharmacology
Nervous System Malformations enzymology
Phenol pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 117
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 32958664
- Full Text :
- https://doi.org/10.1073/pnas.2006883117