Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Mar;53(3):926-34.
doi: 10.1128/AAC.01032-08. Epub 2008 Dec 15.

Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees

Steven S Carroll  1 , Steven Ludmerer, Larry Handt, Kenneth Koeplinger, Nanyan Rena Zhang, Donald Graham, Mary-Ellen Davies, Malcolm MacCoss, Daria Hazuda, David B Olsen
Affiliations

Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees

Steven S Carroll et al. Antimicrob Agents Chemother. 2009 Mar.

Abstract

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated alpha interferon and ribavirin which result in a sustained viral response in 40 to 60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase. A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon, with a 50% effective concentration (EC(50)) of 0.3 microM (EC(90) = 1.3 microM). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose- and time-dependent decreases in plasma viral loads. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg of body weight per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log(10) IU/ml, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log(10), and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV TaqMan assay (20 IU/ml). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least 12 days after dosing ended. The results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
2′-C-Methyl-7-deaza-adenosine (MK-0608).
FIG. 2.
FIG. 2.
Plasma concentrations of MK-0608 in chimpanzees X1 (□) and X2 (⋄) after they received a single dose (A) or seven consecutive daily doses (B) of 1 mg/kg orally. The arithmetic mean is also shown (Δ). The horizontal line depicts the replicon EC50 for MK-0608 (0.3 μM).
FIG. 3.
FIG. 3.
Plasma viral loads during i.v. administration of MK-0608. The compound was dosed in separate experiments at two different dose levels (0.2 mg/kg per day, filled symbols; 2 mg/kg per day, open symbols) to two HCV-infected chimpanzees (X5 [circles] and X3 [squares]). Days are numbered relative to the first day of dosing (day 0). The vertical dashed line indicates the time of administration of the last dose. (A) Plasma samples were periodically collected and viral loads determined using the Versant branched-DNA assay (version 3; Bayer), which has an LOQ of 3,200 copies/ml (3.5 log10, denoted by the horizontal dashed line). Viral loads below the LOQ are graphed at 3,200 copies/ml. (B) Viral loads were also determined from plasma samples from both chimps during dosing at 2 mg/kg using the more sensitive HCV TaqMan assay (Roche), which has an LOQ of 20 IU/ml (1.3 log10 IU/ml, denoted by the horizontal dashed line). Viral loads below the LOQ of the assay are represented at the LOQ. The dashed vertical line represents the time of administration of the last dose.
FIG. 4.
FIG. 4.
Plasma concentrations of the compound 24 h after the 2-mg/kg i.v. dose [C(24h)]. Plasma samples were collected from chimpanzee X5 (○) and chimpanzee X3 (□) 24 h after each dose during the dosing period (days 0 to 6) and for 4 days after dosing ended. Compound concentrations were determined using LC-MS/MS. The dashed line indicates the time of administration of the last dose.
FIG. 5.
FIG. 5.
Plasma viral loads in two HCV-infected chimps dosed at 1 mg/kg MK-0608 orally once daily for 37 days. Plasma viral loads were assessed by the HCV TaqMan assay (Roche), which has an LOQ of 20 (1.3 log10) IU/ml, for chimpanzees X6 (○) and X4 (□), dosed starting at day 0 and ending at day 36. Values that were below the LOQ are graphed as 1.3 log10 IU/ml. The dashed vertical line represents the time of administration of the last dose. The dashed horizontal line represents the lower LOQ.
FIG. 6.
FIG. 6.
Compound concentration in plasma 4.5 h after oral dosing at 1 mg/kg MK-0608 once per day. Compound concentrations were determined from plasma samples collected during dosing at 1 mg/kg once daily by oral administration to chimpanzees X6 (○) and X4 (□). The mean is also shown (Δ). The data demonstrate that some variability in the concentrations at 4.5 h is evident, but no systematic increase or decrease is present. Compound concentrations were below the LOQ (36 nM) on days 42, 49, 56, and 65 for both chimps (not shown).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Afdahl, N., C. O'Brien, E. Godofsky, M. Rodriguez-Torres, S. C. Pappas, P. Pockros, E. Lwitz, N. Bzowej, V. Rustgi, M. Sulkowski, and K. Sherman. 2006. Valopicitabine (NM283), alone or with peg-interferon, compared to peg-interferon/ribavirin (pegIFN/RBV) re-treatment in hepatitis C patients with prior non-response to pegIFN/RBV: week 24 results. J. Hepatol. 44(Suppl. 2):S19.. - PubMed
    1. Beaulieu, P. L., M. Bos, Y. Bousquet, G. Fazal, J. Gauthier, J. Gillard, S. Goulet, S. LaPlante, M. A. Poupart, S. Lefebvre, G. McKercher, C. Pellerin, V. Austel, and G. Kukolj. 2004. Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives. Bioorg. Med. Chem. Lett. 14:119-124. - PubMed
    1. Bukh, J., X. Forns, S. U. Emerson, and R. H. Purcell. 2001. Studies of hepatitis C virus in chimpanzees and their importance for vaccine development. Intervirology 44:132-142. - PubMed
    1. Carroll, S. S., J. E. Tomassini, M. Bosserman, K. Getty, M. W. Stahlhut, A. B. Eldrup, B. Bhat, D. Hall, A. L. Simcoe, R. LaFemina, C. A. Rutkowski, B. Wolanski, Z. Yang, G. Migliaccio, R. De Francesco, L. C. Kuo, M. MacCoss, and D. B. Olsen. 2003. Inhibition of hepatitis C virus RNA replication by 2′-modified nucleoside analogs. J. Biol. Chem. 278:11979-11984. - PubMed
    1. Chan, L., O. Pereira, T. J. Reddy, S. K. Das, C. Poisson, M. Courchesne, M. Proulx, A. Siddiqui, C. G. Yannopoulos, N. Nguyen-Ba, C. Roy, D. Nasturica, C. Moinet, R. Bethell, M. Hamel, L. L'Heureux, M. David, O. Nicolas, P. Courtemanche-Asselin, S. Brunette, D. Bilimoria, and J. Bedard. 2004. Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides. Bioorg. Med. Chem. Lett. 14:797-800. - PubMed

MeSH terms