Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivatives

Salim, Mohammed T.A.; Aoyama, Hiroshi; Sugita, Kazuyuki; Watashi, K; Wakita, Takaji; Hamasaki, Takayuki; Okamoto, Masato; Urata, Yasuo; Hashimoto, Yuichi; Baba, Masanori

doi:10.1016/j.bbrc.2011.10.153

Cited by 10 publications

(10 citation statements)

References 41 publications

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“…The assay methods for drug cytotoxicity have been described previously (Salim et al, 2011). Briefly, LucNeo#2 and NNC#2 cells (5 × 10 3 cells/well) were cultured in a 96-well plate in the absence of G418 and in the presence of various dilutions of Alpha-zam.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

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Selective Inhibition of Hepatitis C Virus Replication by Alpha-Zam, a Nigella Sativa Seed Formulation

Oyero¹,

Toyama²,

Mitsuhiro³

et al. 2016

Afr J Tradit Complement Altern Med

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Background: Hepatitis C virus (HCV) infection became curable because of the development of direct acting antivirals (DAAs). However, the high cost of DAAs has greatly impeded their potential impact on the treatment of HCV infection. As a result, hepatitis C will continue to cause substantial morbidity, and mortality among chronically infected individuals in low and middle income countries. Thus, urgent need exists for developing cheaper drugs available to hepatitis C patients in these countries. Materials and Methods: Alpha-zam, an indigenous herbal formulation from Nigella sativa seed, was examined for its anti-HCV activity and cytotoxicity in genotype 1b HCV replicon cells. The antiviral activity was determined by luciferase expression and viral RNA synthesis, while the cytotoxicity was assessed by viable cell number and glyceraldehyde-3-phosphate dehydrogenase RNA synthesis in the replicon cells. Results: Alpha-zam was found to be a selective inhibitor of HCV replication. The 50% effective dilution and 50% cytotoxic dilution of Alpha-zam were 761-and < 100-fold, respectively, in the subgenomic replicon cells LucNeo#2. Its selective inhibition of HCV was also confirmed by HCV RNA levels in LucNeo#2 and in the full-genome HCV replicon cells NNC#2 using real-time reverse transcriptase polymerase chain reaction. Furthermore, the anti-HCV activity of Alpha-zam was not due to the induction of interferon. Conclusion: Alpha-zam selectively inhibits HCV replication and therefore has potential for a novel antiviral agent against HCV infection.

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Section: Cytotoxicity Assaysmentioning

confidence: 99%

“…The anti-HCV activity of alpha-zam was determined by a modification of the described methods (Windisch et al, 2005;Salim et al, 2011). Briefly, LucNeo#2 cells (5 × 10 3 cells/well) were cultured in a 96-well plate in the absence of G418 and in the presence of various dilutions of Alpha-zam.…”

Section: Antiviral Assaysmentioning

confidence: 99%

Selective Inhibition of Hepatitis C Virus Replication by Alpha-Zam, a Nigella Sativa Seed Formulation

Oyero¹,

Toyama²,

Mitsuhiro³

et al. 2016

Afr J Tradit Complement Altern Med

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“…23 The carboxamide motifs in 12−29 are aromatic, 30−48 are aliphatic, and 49−53 are benzyl. Anti-HCV activity was determined by their ability to reduce luciferase activity in HCV RNA replicons.…”

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confidence: 99%

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Konreddy

Toyama

Ito

et al. 2013

ACS Med. Chem. Lett.

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High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold I based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure−activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (17−19, 21−22, 24− 25, and 49) with EC 50 ranging 0.15 to 0.40 μM, the aryl group at C-6 position of α-pyranone were unsubstituted. In particular, 25 demonstrated potential anti-HCV activity with EC 50 of 0.18 μM in cell based HCV replicon system with lower cytotoxicity (CC 50 > 20 μM) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action. KEYWORDS: Hepatitis C virus, non-nucleoside inhibitor, α-pyranone carboxamide H epatitis C virus (HCV) is a single stranded 9.6 kb RNA virus of the Flaviviridae family predominantly infecting hepatocytes. HCV infection is silent and in long-term may lead to serious liver disease, including fibrosis and cirrhosis followed by hepatocellular carcinoma. 1,2 The prophylactic treatment has been of very limited success, 3 and so far no vaccine is available. 4 A serious health threat has been realized, and a series of investigations are underway to discover direct acting antivirals (DAAs) as promising anti-HCV agents. 5 The potential molecules 1−4 (Figure 1) belonging to DAAs target mainly three viral enzymes: (i) protease NS3/4A, (ii) replicase factor NS5A, and (iii) HCV RNA-dependent RNA polymerase (HCV RdRp) NS5B. 6 The medicinal chemistry approaches with breakthrough exploration in HCV biology 7 were translated recently into first generation DAAs, boceprevir 8 and telaprevir 9 (protease inhibitors) approved by US FDA. Several new generation protease inhibitors are under serious investigations to combat the challenges associated with anti-HCV therapy. 10,11 The current standard of care (SoC) for HCV treatment includes one of the approved protease inhibitors combined with pegylated interferon-α (PegIFN) and ribavirin (RBV).The new regimen improves sustained viral response (SVR) rates to ∼75%; 8,9 however, it also adds side effect burden to patients. The use of PegIFN/RBV is associated with severe side effects followed by treatment discontinuation and contraindication. 12 Overall, drug-resistance, drug−drug interactions, and side effects are major concerns, 13 which demand effective PegIFN/RBV free regimen. In addition to recent success in protease inhibitors, 10,11 parallel research efforts are in progress to discover nucleoside inhibitors (NIs) to find novel DAAs to target HCV RdRp. 14,15 Similarly, several non-nucleoside allosteric inhibitors are in development phase, which may provide a choice of combination with other DAAs to discover

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“…PARP family inhibitors sensitize cancer cells for drug and radiation treatment and are in clinical trials as cancer therapeutics (23). PARP proteins have been associated with inflammation, neuronal death and ischemia, and novel phenanthridinone derivatives are potent and selective inhibitors of hepatitis C virus replication in vitro (24). Oxaprozin is a propionic acid derivative widely used in the treatment of inflammatory and painful diseases of rheumatic and non-rheumatic basis (25).…”

Section: Resultsmentioning

confidence: 99%

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

Zerbini

Bhasin

Vasconcellos

et al. 2014

Molecular Cancer Therapeutics

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While early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of the current study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anti-cancer therapy. Here we demonstrate that one of the drugs predicted to revert the RCC gene signature towards normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and p-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most ccRCC patients for the set of high scoring drugs. Most of the selected high scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for VHL negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for metastatic ccRCC patients and support our notion that IBA combined with C-MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy.

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Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivatives

Cited by 10 publications

References 41 publications

Selective Inhibition of Hepatitis C Virus Replication by Alpha-Zam, a Nigella Sativa Seed Formulation

Selective Inhibition of Hepatitis C Virus Replication by Alpha-Zam, a Nigella Sativa Seed Formulation

Synthesis and Anti-HCV Activity of 4-Hydroxyamino α-Pyranone Carboxamide Analogues

Computational Repositioning and Preclinical Validation of Pentamidine for Renal Cell Cancer

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