Small Molecule and Biologic Inhibitors of Hepatitis C Virus: A Symbiotic Approach

Vecchio, Del; Rt, Sarisky

doi:10.2174/138955706778742786

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…NS5B shares very limited sequence homology with cellular polymerases; hence, it is an attractive target for the development of antiviral therapy. Several classes of inhibitors, including nucleosides, nonnucleosides, and pyrophosphate mimics, that target this viral enzyme have been developed (3,13). We have developed nonnucleoside inhibitors in the benzothiadiazine class and demonstrated their inhibitory activities in biochemical assays using purified polymerases as well as in vitro using the subgenomic replicon system (16,19).…”

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confidence: 99%

Activity of a Potent Hepatitis C Virus Polymerase Inhibitor in the Chimpanzee Model

Chen

et al. 2007

Antimicrob Agents Chemother

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A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log 10 copies RNA/ml for genotype 1a-and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.Hepatitis C virus (HCV) is a small, enveloped virus that contains a single-stranded, positive-sense RNA (2). The World Health Organization estimates that approximately 170 million people worldwide are infected with HCV (25). Of these, 130 million are chronic HCV carriers at risk for the development of liver cirrhosis and/or liver cancer. In the United States, HCV infection leading to liver failure is the major indication for liver transplantation (4, 12). The current standard of care, which consists of a combination of pegylated interferon and ribavirin, provides good clinical efficacy for patients infected with genotype 2 and 3 viruses but is less effective for patients infected with genotype 1 viruses. Subgenotypes 1a and 1b constitute the most commonly found isolates in the United States, Japan, and Western Europe; and thus, the development of effective treatments against genotype 1 viruses presents a pressing need.HCV nonstructural protein 5B (NS5B) encodes a viral RNA-dependent RNA polymerase, an essential enzyme responsible for the replication of the viral genome. NS5B shares very limited sequence homology with cellular polymerases; hence, it is an attractive target for the development of antiviral therapy. Several classes of inhibitors, including nucleosides, nonnucleosides, and pyrophosphate mimics, that target t...

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Activity of a Potent Hepatitis C Virus Polymerase Inhibitor in the Chimpanzee Model

Chen

et al. 2007

Antimicrob Agents Chemother

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“…-Viral-polymerase inhibitors: These are another important class of antiviral agents, and comprise nucleoside, non-nucleoside and pyrophosphate mimics, and other classes of agents (258). Non-nucleoside inhibitors have been tested in vitro by using the replicon system, and in biochemical assays by using purified viral polymerase (259,260), with positive results.…”

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An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 1. Validity of the Chimpanzee Model

Bailey

2010

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The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major scientific, ethical, economic and practical caveats. It has made a relatively negligible contribution to knowledge of, and tangible progress against, the hepatitis C virus compared to non-chimpanzee research, and must be considered scientifically redundant, given the array of alternative methods of inquiry now available. The continuation of chimpanzee use in hepatitis C research adversely affects scientific progress, as well as chimpanzees and humans in need of treatment. Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.

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Prospects for the creation of new antiviral drugs based on glycyrrhizic acid and its derivatives (a review)

et al. 2009

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The review is devoted to the problem of creating new antiviral drugs based on glycyrrhizic acid (GA), the major triterpene glycoside extracted from roots of common and Ural licorice (Glycyrrhiza glabra L. and G. uralensis Fisher, respectively). Published data on the natural GA sources, antiviral activity of GA and its derivatives, clinical applications of GA-based drugs, and the properties of GA-containing biologically active nutrient additives are summarized. Possible mechanisms of the antiviral activity of GA and its derivatives are examined. It is shown that chemical modification of GA is a promising way of designing new highly active antiviral drugs for the prophylaxis and treatment of HIV, hepatitis B and C, corona-virus, and herpes simplex virus infections.

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Small Molecule and Biologic Inhibitors of Hepatitis C Virus: A Symbiotic Approach

Cited by 3 publications

References 21 publications

Activity of a Potent Hepatitis C Virus Polymerase Inhibitor in the Chimpanzee Model

Activity of a Potent Hepatitis C Virus Polymerase Inhibitor in the Chimpanzee Model

An Assessment of the Use of Chimpanzees in Hepatitis C Research Past, Present and Future: 1. Validity of the Chimpanzee Model

Prospects for the creation of new antiviral drugs based on glycyrrhizic acid and its derivatives (a review)

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