Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors

Ikegashira, Kazutaka; Oka, Takahiro; Hirashima, Shin‐ichi; Noji, Satoru; Yamanaka, Hiroshi; Hara, Yoshinori; Adachi, Tsutomu; Tsuruha, Jun-Ichiro; Doi, Satoki; Hase, Yasunori; Noguchi, Tōru; Ando, Izuru; Ogura, Naoto; Ikeda, Satoru; Hashimoto, Harukichi

doi:10.1021/jm0610245

Cited by 100 publications

(103 citation statements)

References 16 publications

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“…The NNI-1 site is almost identical for the two enzymes. In the absence of an NNI-1 ligand, helix A of the mobile ⌳1 loop occupies the known indole-binding site (10,20), as has been observed in other structures (6,26,32,47) on May 9, 2018 by guest http://jvi.asm.org/ mational preference at this position could impact inhibitor affinity; this is, however, highly speculative and requires further structural studies for clarification. Interestingly, the Ala499 variant has been suggested as a possible cause of benzimidazole resistance (42).…”

Section: Analysis Of Nni-1 -2 and -4mentioning

confidence: 83%

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Nyanguile¹,

Devogelaere²,

Vijgen³

et al. 2010

J Virol

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The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor-and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.

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Section: Analysis Of Nni-1 -2 and -4mentioning

confidence: 83%

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Nyanguile¹,

Devogelaere²,

Vijgen³

et al. 2010

J Virol

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“…Nonnucleoside polymerase inhibitors (NNIs) interact with four distinct allosteric sites on HCV polymerase (4). We previously reported the discovery of several HCV polymerase inhibitors with a benzimidazole and indole core based on highthroughput screening and structure-based drug design (14,15,18,19).…”

Section: H Epatitis C Virus (Hcv) Is the Major Cause Of Posttransfusimentioning

confidence: 99%

“…The cocrystallization analysis of JTK-853 with HCV polymerase genotype 1b BK strain was performed as previously described (1,18). HCV polymerase with a truncation of 21 amino acids at the C terminus, designated NS5B570, was used in this study because the production of soluble full-length NS5B protein was very difficult (1,17,32,33).…”

Section: Structural Analysismentioning

confidence: 99%

Preclinical Characterization of JTK-853, a Novel Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

Ando

Adachi

Ogura

et al. 2012

Antimicrob Agents Chemother

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“…indoles as NS5B inhibitors [72]. The 6, 5-bicyclic core and the C-2 ring were bridged to get a potent compound.…”

Section: Indolesmentioning

confidence: 99%

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Polamreddy

Vishwakarma

Gundla

2016

Int J Pharm Pharm Sci

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Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

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Discovery of Conformationally Constrained Tetracyclic Compounds as Potent Hepatitis C Virus NS5B RNA Polymerase Inhibitors

Cited by 100 publications

References 16 publications

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Preclinical Characterization of JTK-853, a Novel Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

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