Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses

Borowski, Peter; Deinert, Johanna; Schalinski, Sarah; Bretner, Maria; Ginalski, Krzysztof; Kulikowski, Tadeusz; Shugar, David

doi:10.1046/j.1432-1033.2003.03540.x

Cited by 118 publications

(113 citation statements)

References 45 publications

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“…Since the helicase domain of HCV NS3 is probably crucial for the proliferation of HCV, identification of inhibitors for the helicase has been employed mainly through random screening of small molecules (Borowski et al 2003) or phage-display antibody screening (Artsaenko et al 2003). However, potential limitations of those molecules would stem from nonspecificity or low affinity to the target protein.…”

Section: Discussionmentioning

confidence: 99%

Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus

Hwang¹,

Cho²,

Yeo³

et al. 2004

RNA

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Hepatitis C virus (HCV)-encoded nonstructural protein 3 (NS3) possesses protease, NTPase, and helicase activities, which are considered essential for viral proliferation. Thus, HCV NS3 is a good putative therapeutic target protein for the development of anti-HCV agents. In this study, we isolated specific RNA aptamers to the helicase domain of HCV NS3 from a combinatorial RNA library with 40-nucleotide random sequences using in vitro selection techniques. The isolated RNAs were observed to very avidly bind the HCV helicase with an apparent K d of 990 pM in contrast to original pool RNAs with a K d of >1 µM. These RNA ligands appear to impede binding of substrate RNA to the HCV helicase and can act as potent decoys to competitively inhibit helicase activity with high efficiency compared with poly(U) or tRNA. The minimal binding domain of the ligands was determined to evaluate the structural features of the isolated RNA molecules. Interestingly, part of binding motif of the RNA aptamers consists of similar secondary structure to the 3-end of HCV negative-strand RNA. Moreover, intracellular NS3 protein can be specifically detected in situ with the RNA aptamers, indicating that the selected RNAs are very specific to the HCV NS3 helicase. Furthermore, the RNA aptamers partially inhibited RNA synthesis of HCV subgenomic replicon in Huh-7 hepatoma cell lines. These results suggest that the RNA aptamers selected in vitro could be useful not only as therapeutic and diagnostic agents of HCV infection but also as a powerful tool for the study of HCV helicase mechanism.

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Section: Discussionmentioning

confidence: 99%

Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus

Hwang¹,

Cho²,

Yeo³

et al. 2004

RNA

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“…Interestingly, none of these inhibit the JEV helicase, even though it is closely related to WNV helicase. Under the conditions used, none of the compounds inhibited helicase-catalyzed ATP hydrolysis, suggesting that they may bind to another NTP-binding site or interact with the nucleic acid substrates [186].…”

Section: Sf2 Helicase Inhibitorsmentioning

confidence: 96%

“…Such compounds would not competitively inhibit ATP hydrolysis, but would modulate ATP hydrolysis and/or unwinding by binding an allosteric site. Several such compounds recently have been reported [186][187][188]. Representatives are shown along with HMC-HO4 in Fig.…”

Section: Sf2 Helicase Inhibitorsmentioning

confidence: 99%

“…A series of halogenated benzimidazoles and benzotriazoles, which were originally reported as HCV inhibitors in patents by Viropharma Inc., were recently examined for their ability to inhibit HCV, WNV, and JEV helicases [186]. Dichloro(ribofuranosyl)benzotriazole (DRBT) and dichloro(ribofuranosyl)benzimidazole (DRB) are nucleoside analogs, while tetrachlorobenzotriazole (TCBT) and tetrabromobenzotriazole (TBBT) are base analogs.…”

Section: Sf2 Helicase Inhibitorsmentioning

confidence: 99%

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Understanding Helicases as a Means of Virus Control

Frick¹,

Lam²

2006

CPD

101

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Helicases are promising antiviral drug targets because their enzymatic activities are essential for viral genome replication, transcription, and translation. Numerous potent inhibitors of helicases encoded by herpes simplex virus, severe acute respiratory syndrome coronavirus, hepatitis C virus, Japanese encephalitis virus, West Nile virus, and human papillomavirus have been recently reported in the scientific literature. Some inhibitors have also been shown to decrease viral replication in cell culture and animal models. This review discusses recent progress in understanding the structure and function of viral helicases to help clarify how these potential antiviral compounds function and to facilitate the design of better inhibitors. The above helicases and all related viral proteins are classified here based on their evolutionary and functional similarities, and the key mechanistic features of each group are noted. All helicases share a common motor function fueled by ATP hydrolysis, but differ in exactly how the motor moves the protein and its cargo on a nucleic acid chain. The helicase inhibitors discussed here influence rates of helicase-catalyzed DNA (or RNA) unwinding by preventing ATP hydrolysis, nucleic acid binding, nucleic acid release, or by disrupting the interaction of a helicase with a required cofactor.

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“…4,5,6,7-Tetrabromobenzotriazole (TBBT) and 5,6-dichloro-1-(␤-D-ribofuranosyl)benzotriazole (DRBT) were reported to inhibit HCV helicase in an in vitro assay (50% inhibitory concentration of 20 to 60 M for TBBT [2] and 0.1 to 1.5 M for DRBT [2], depending on the nature of the template). TBBT resulted in some inhibitory effect in the replicon system which was comparable to the inhibition in the enzymatic assay.…”

mentioning

confidence: 99%

Comparative In Vitro Anti-Hepatitis C Virus Activities of a Selected Series of Polymerase, Protease, and Helicase Inhibitors

Paeshuyse

Vliegen

Coelmont

et al. 2008

Antimicrob Agents Chemother

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We report here a comparative study of the anti-hepatitis C virus (HCV) activities of selected (i) nucleoside polymerase, (ii) nonnucleoside polymerase, (iii) ␣,␥-diketo acid polymerase, (iv) NS3 protease, and (v) helicase inhibitors, as well as (vi) cyclophilin binding molecules and (vii) alpha 2b interferon in four different HCV genotype 1b replicon systems.Worldwide, more than 170 million people are chronically infected with hepatitis C virus (HCV) and are thus at increased risk of developing serious, life-threatening liver disease. Current standard therapy for chronic hepatitis C consists of pegylated interferon in combination with ribavirin (26). Unfortunately, this therapy results in a sustained virological response in only about 50 to 60% of the patients treated and is associated with serious side effects. There is an urgent need for new therapeutic strategies (10).Small-molecule inhibitors that target, in particular, the NS3 protease or the NS5B RNA-dependent RNA polymerase (RdRp) have been pursued as potential new therapies. BILN 2061 (culprivir), a peptidomimetic inhibitor of the HCV NS3 protease, was the first selective inhibitor of HCV to be administered to patients chronically infected with HCV (genotype 1). Administration of the compound resulted in a rapid and pronounced decline in viral replication (11, 12), but the drug was not developed further because of toxicity issues (11).Following the pioneering studies with BILN 2061, numerous anti-HCV compounds progressed toward clinical studies; three other NS3 protease inhibitors, i.e., VX-950 (telaprevir), SCH 503034 (boceprevir), and TMC435350, entered clinical trials. VX-950 has shown good efficacy both in monotherapy (29) and in combination with the current standard therapy (8) and is currently in phase II clinical studies.

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Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses

Cited by 118 publications

References 45 publications

Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus

Isolation of specific and high-affinity RNA aptamers against NS3 helicase domain of hepatitis C virus

Understanding Helicases as a Means of Virus Control

Comparative In Vitro Anti-Hepatitis C Virus Activities of a Selected Series of Polymerase, Protease, and Helicase Inhibitors

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