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ACS Infect Dis. 2019 May 10;5(5):655-658. doi: 10.1021/acsinfecdis.8b00045. Epub 2018 Mar 22.

Chemical Approaches to Inhibiting the Hepatitis B Virus Ribonuclease H.

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Department of Molecular Microbiology and Immunology and Saint Louis University Liver Center, School of Medicine , Saint Louis University , 1100 S. Grand Blvd. , Saint Louis , Missouri 63104 , United States.
Department of Pharmaceutical Chemistry, School of Health Sciences, Faculty of Pharmacy , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou, Athens , GR-15771 , Greece.
Department of Chemistry , Saint Louis University , Monsanto Hall 125, 3501 Laclede Avenue , St. Louis , Missouri 63103 , United States.
Department of Chemistry , Brooklyn College, The City University of New York , Brooklyn , New York 11210 , United States.
PhD Program in Chemistry, The Graduate Center , The City University of New York , New York , New York 10016 , United States.


Hepatitis B virus (HBV) chronically infects >250 million people and kills nearly a million annually, and current antivirals cannot clear the infection or adequately suppress disease. The virus replicates by reverse transcription, and the dominant antiviral drugs are nucleos(t)ide analogs that target the viral reverse transcriptase. We are developing antivirals targeting the other essential viral enzymatic activity, the ribonuclease H (RNaseH). HBV RNaseH inhibitors with efficacies in the low micromolar to nanomolar range against viral replication in culture have been identified in the α-hydroxytropolone and hydroxyimide chemotypes. Here, we review the promise of RNaseH inhibitors, their current structure-activity relationships, and challenges to optimizing the inhibitors into leads for clinical assessment.

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