The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two differentHCVreplicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Poliopol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the ΔC55-1b and ΔC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.

Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors / J.M. Ontoria, E.H. Rydberg, S. Di Marco, L. Tomei, B. Attenni, S. Malancona, J.I. Martin Hernando, N. Gennari, U. Koch, F. Narjes, M. Rowley, V. Summa, S.S. Carroll, D.B. Olsen, R. De Francesco, S. Altamura, G. Migliaccio, A. Carfì. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52:16(2009), pp. 5217-5227.

Identification and biological evaluation of a series of 1H-benzo[de]isoquinoline-1,3(2H)-diones as hepatitis C virus NS5B polymerase inhibitors

R. De Francesco;
2009

Abstract

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for inhibition. Herein, we present 1H-benzo[de]isoquinoline-1,3(2H)-diones as a new series of selective inhibitors of HCV NS5B polymerase. The HTS hit 1 shows submicromolar potency in two differentHCVreplicons (1b and 2b) and displays no activity on other polymerases (HIV-RT, Poliopol, GBV-b-pol). These inhibitors act during the pre-elongation phase by binding to NS5B non-nucleoside binding site Thumb Site II as demonstrated by crystal structure of compound 1 with the ΔC55-1b and ΔC21-2b enzymes and by mutagenesis studies. SAR in this new series reveals inhibitors, such as 20, with low micromolar activity in the HCV replicon and with good activity/toxicity window in cells.
Dependent RNA-polymerase; nonnucleoside inhibitors; allosteric inhibitors; HCVNS5B polymerase; crystal-structure; replicon variants; recent progress; active-site; mechanism; binding
Settore BIO/19 - Microbiologia Generale
Settore BIO/13 - Biologia Applicata
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/634740
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