Antiviral Res. 2019 Sep 21:104613. doi: 10.1016/j.antiviral.2019.104613. [Epub ahead of print]
Ribonuclease H, an unexploited target for antiviral intervention against HIV and hepatitis B virus.
Tramontano E1, Corona A2, Menendez-Arias L3.
Author information
1
Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy. Electronic address: [email protected].
2
Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
3
Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid), Madrid, Spain. Electronic address: [email protected].
Abstract
Ribonucleases H (RNases H) are endonucleolytic enzymes, evolutionarily related to retroviral integrases, DNA transposases, resolvases and numerous nucleases. RNases H cleave RNA in RNA/DNA hybrids and their activity plays an important role in the replication of prokaryotic and eukaryotic genomes, as well as in the replication of reverse-transcribing viruses. During reverse transcription, the RNase H activity of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) degrades the viral genomic RNA to facilitate the synthesis of viral double-stranded DNA. HIV and HBV reverse transcriptases contain DNA polymerase and RNase H domains that act in a coordinated manner to produce double-stranded viral DNA. Although RNase H inhibitors have not been developed into licensed drugs, recent progress has led to the identification of a number of small molecules with inhibitory activity at low micromolar or even nanomolar concentrations. These compounds can be classified into metal-chelating active site inhibitors and allosteric inhibitors. Among them, α-hydroxytropolones, N-hydroxyixoquinolinediones and N-hydroxypyridinediones represent chemotypes active against both HIV and HBV RNases H. In this review we summarize recent developments in the field including the identification of novel RNase H inhibitors, compounds with dual activity, broad specificity and efforts to decrease their toxicity.