Identification of Small-Molecule Inhibitors of the Ribonuclease H2 Enzyme

被引:9
作者
White, Rachel [1 ]
Saxty, Barbara [2 ]
Large, Jonathan [2 ]
Kettleborough, Catherine A. [2 ]
Jackson, Andrew P. [1 ]
机构
[1] Univ Edinburgh, MRC IGMM, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
[2] MRC Technol, Ctr Therapeut Discovery, London, England
关键词
nuclease; ribonuclease H2; high-throughput screen; inhibitors; Aicardi-GoutiSres syndrome; AICARDI-GOUTIERES-SYNDROME; RNASE H2; EXONUCLEASE TREX1; GENOME INTEGRITY; DNA; MUTATIONS; PURIFICATION; COMPLEX; CELLS;
D O I
10.1177/1087057113476550
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Ribonuclease H2 (RNase H2) is a nuclease that specifically hydrolyzes RNA residues in RNA-DNA hybrids. Mutations in the RNase H2 enzyme complex have been identified in the genetic disorder Aicardi-GoutiSres syndrome (AGS), which has similarities to the autoimmune disease systemic lupus eryrthrematosis (SLE). The RNase H2 enzyme has also been recently implicated as a key genome surveillance enzyme. Therefore, small-molecule modulators of RNase H2 activity may have utility in therapeutics and as tools to investigate the cellular functions of RNase H2. A fluorescent quench assay, measuring cleavage of an RNA-DNA duplex substrate by recombinant RNase H2, was developed into a high-throughput format and used to screen a 48 560 compound library. A hit validation strategy was subsequently employed, leading to the identification of two novel inhibitor compounds with in vitro nanomolar range inhibition of RNase H2 activity and > 100-fold selectivity compared with RNase H type 1. These compounds are the first small-molecule inhibitors of RNase H2 to be reported. They and their derivatives should provide the basis for the development of tool compounds investigating the cellular functions of the RNase H2 enzyme, and, potentially, for pharmacological manipulation of nucleic acid-mediated immune responses.
引用
收藏
页码:610 / 620
页数:11
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