Τίτλος:
Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors. © 2017 Elsevier B.V.
Συγγραφείς:
Edwards, T.C.
Lomonosova, E.
Patel, J.A.
Li, Q.
Villa, J.A.
Gupta, A.K.
Morrison, L.A.
Bailly, F.
Cotelle, P.
Giannakopoulou, E.
Zoidis, G.
Tavis, J.E.
Περιοδικό:
Antiviral Research
Λέξεις-κλειδιά:
antivirus agent; flutimide; heteroduplex; hydroxyl group; isoquinoline derivative; ribonuclease H; unclassified drug; antivirus agent; capsid protein; flutimide; piperazine derivative; ribonuclease HI; virus DNA, antiviral activity; Article; concentration response; controlled study; DNA RNA hybridization; DNA strand; drug inhibition; drug screening; EC50; Hep-G2 cell line; Hepatitis B virus; human; human cell; nonhuman; oxygenation; priority journal; structure activity relation; virus inhibition; animal; antagonists and inhibitors; chemistry; Chlorocebus aethiops; DNA replication; drug development; drug effects; enzymology; genetics; hepatitis B; Hepatitis B virus; microbial sensitivity test; physiology; preclinical study; tumor cell line; Vero cell line; virology; virus replication, Animals; Antiviral Agents; Capsid Proteins; Cell Line, Tumor; Cercopithecus aethiops; DNA Replication; DNA, Viral; Drug Discovery; Drug Evaluation, Preclinical; Hepatitis B; Hepatitis B virus; Humans; Microbial Sensitivity Tests; Piperazines; Ribonuclease H; Structure-Activity Relationship; Vero Cells; Virus Replication
DOI:
10.1016/j.antiviral.2017.04.012
