Identification of PARN nuclease activity inhibitors by computational-based docking and high-throughput screening

Poly(A)-specific ribonuclease (PARN) is a 3′-exoribonuclease that removes poly(A) tails from the 3′ end of RNAs. PARN is known to deadenylate some ncRNAs, including hTR, Y RNAs, and some miRNAs and thereby enhance their stability by limiting the access of 3′ to 5′ exonucleases recruited by oligo(A)...

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Published inScientific reports Vol. 13; no. 1; p. 5244
Main Authors Huynh, Thao Ngoc, Shukla, Siddharth, Reigan, Philip, Parker, Roy
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 31.03.2023
Nature Publishing Group
Nature Portfolio
Subjects
631/154
631/337
Abl protein
Adenosine
BCR protein
Computer applications
Exoribonucleases - metabolism
Fusion protein
High-throughput screening
High-Throughput Screening Assays
Humanities and Social Sciences
Humans
Inhibitors
Kinases
MicroRNAs
Molecular Docking Simulation
mRNA
multidisciplinary
Mutation
Nuclease
p53 Protein
Pharmaceutical sciences
Poly(A)-specific ribonuclease
Polyadenine
Proteins
Ribonuclease
RNA, Messenger - metabolism
Science
Science (multidisciplinary)
Tumor Suppressor Protein p53 - genetics
Tumors
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Summary:Poly(A)-specific ribonuclease (PARN) is a 3′-exoribonuclease that removes poly(A) tails from the 3′ end of RNAs. PARN is known to deadenylate some ncRNAs, including hTR, Y RNAs, and some miRNAs and thereby enhance their stability by limiting the access of 3′ to 5′ exonucleases recruited by oligo(A) tails. Several PARN-regulated miRNAs target p53 mRNA, and PARN knockdown leads to an increase of p53 protein levels in human cells. Thus, PARN inhibitors might be used to induce p53 levels in some human tumors and act as a therapeutic strategy to treat cancers caused by repressed p53 protein. Herein, we used computational-based molecular docking and high-throughput screening (HTS) to identify small molecule inhibitors of PARN. Validation with in vitro and cell-based assays, identified 4 compounds, including 3 novel compounds and pyrimidopyrimidin-2-one GNF-7, previously shown to be a Bcr-Abl inhibitor, as PARN inhibitors. These inhibitors can be used as tool compounds and as lead compounds for the development of improved PARN inhibitors.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-32039-z