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Title: The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors

Journal Article · · Journal of Biological Chemistry
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  1. GlaxoSmithKline, Research Triangle Park, NC (United States)
  2. GlaxoSmithKline, Waltham, MA (United States)
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2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2–5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2–5A. Phosphodiesterase 12 (PDE12) was the first cellular 2–5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2–5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2–5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. As a result, the crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE
OSTI ID:
1233752
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 32; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 52 works
Citation information provided by
Web of Science

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Cited By (10)

The structure of human Nocturnin reveals a conserved ribonuclease domain that represses target transcript translation and abundance in cells journal June 2018
OAS-RNase L innate immune pathway mediates the cytotoxicity of a DNA-demethylating drug journal February 2019
Imaging of PDE2- and PDE3-Mediated cGMP-to-cAMP Cross-Talk in Cardiomyocytes journal January 2018
Maturation of selected human mitochondrial tRNAs requires deadenylation journal July 2017
The metabolites NADP+ and NADPH are the targets of the circadian protein Nocturnin (Curled) journal May 2019
DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences journal June 2018
DNA-encoded chemistry: enabling the deeper sampling of chemical space journal December 2016
Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries journal October 2018
The Metabolites NADP + and NADPH are the Targets of the Circadian Protein Nocturnin (Curled) journal January 2019
Maturation of selected human mitochondrial tRNAs requires deadenylation text January 2017

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60 APPLIED LIFE SCIENCES
antiviral agent
gene knockout
innate immunity
interferon
protein structure