Design, synthesis, and antiviral properties of 4′-substituted ribonucleosides as inhibitors of hepatitis C virus replication: The discovery of R1479

Smith, David B.; Martin, Joseph A.; Klumpp, Klaus; Baker, Stewart; Blomgren, Peter; Devos, René; Granycome, Caroline; Hang, Julie Q.; Hobbs, Christopher; Jiang, Wen-Rong; Laxton, Carl; Pogam, Sophie Le; Lévêque, Vincent; Ma, Han; Maile, G.; Merrett, John H.; Pichota, Arkadius; Sarma, Keshab; Smith, Mark A.; Swallow, Steven; Symons, Julian; Vesey, D.; Nájera, Isabel; Cammack, Nick

doi:10.1016/j.bmcl.2007.02.004

Cited by 94 publications

(83 citation statements)

References 19 publications

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“…If such a drug becomes available for treating HCV infections, it could also be used "offlabel" to treat PV infection. However, 4′-azidocytidine, a potent inhibitor of HCV replication (37), was devoid of anti-PV activity up to the highest concentrations tested. As reported before and confi rmed here, ribavirin proved to be a relatively weak inhibitor of PV replication (TIs >1.8).…”

Section: Discussion and Perspectivesmentioning

confidence: 95%

Potential Use of Antiviral Agents in Polio Eradication

Palma

Pürstinger

Wimmer

et al. 2008

Emerg. Infect. Dis.

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Section: Discussion and Perspectivesmentioning

confidence: 95%

Potential Use of Antiviral Agents in Polio Eradication

Palma

Pürstinger

Wimmer

et al. 2008

Emerg. Infect. Dis.

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“…The increased base pairing stability of G:C base pairs may therefore be required to allow sufficient binding affinity of these compounds in the NS5B active site to confer measurable inhibitory potency. Based on the discovery that 4Ј-substitutions on ribonucleosides could provide potent and selective inhibitors of HCV RNA synthesis (6,7) and assuming that additional interactions with the 4Ј-substituent could further compensate for the loss of ␣-hydroxy interaction, the effect of such substitutions on deoxyribonucleosides was assessed. The results were unexpected in their magnitude.…”

Section: Discussionmentioning

confidence: 99%

“…2Ј-␣-FluoroNTPs showed antiviral potencies against influenza virus and were substrates for the RNA-dependent RNA polymerase of influenza virus (35,36). 2Ј-␣-Fluorocytidine was also assessed as an inhibitor of HCV replication but was a potent inhibitor of cell proliferation in the HCV replicon system (7,37). The addition of a 2Ј-␤-methyl substituent resulted in the discovery of PSI-6130 (2Ј-␣-fluoro-2Ј-␤-methylcytidine), a potent inhibitor of HCV replication (38).…”

Section: Discussionmentioning

confidence: 99%

“…Previously, R1479 was identified as a potent and selective inhibitor of HCV replication in cell culture (6,7). R1626, a prodrug of 4Ј-azidocytidine, is presently in phase II clinical development.…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 99%

“…However, the incorporation efficiency of ara-CTP was 140-fold lower as compared with CTP, in line with an important interaction of the 2Ј-␣-hydroxy group. Earlier, we discovered that 4Ј-substituents on ribonucleoside analogs may pick up additional binding interactions in the HCV polymerase active site, with 4Ј-azido being the most effective to allow productive binding to both HCV polymerase and human nucleoside kinases (6,7,9). The addition of a 4Ј-azido moiety to the ara-CTP molecule resulted in an unexpected 15-30-fold increase in inhibitory potency of 2Ј-␣-deoxy-2Ј-␤-hydroxy-4Ј-azido-CTP (RO-9187-TP) as compared with 2Ј-␣-deoxy-ara-CTP.…”

Section: ј-Substitution Can Increase the Inhibitory Potency Of 2ј-␣-mentioning

confidence: 99%

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2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2-␣-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of ␣-hydroxy moieties. 2-Deoxy-2-␤-fluoro-4-azidocytidine (RO-0622) and 2-deoxy-2-␤-hydroxy-4-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC 50 ‫؍‬ 171 ؎ 12 nM and 24 ؎ 3 nM for RO-9187 and RO-0622, respectively; CC 50 >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4-azidocytidine) or 2-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC 50 values 8 -150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2-␣-deoxy-4-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection. Hepatitis C virus (HCV)3 infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation. Current treatment options available to HCV-infected persons have limitations with regard to efficacy and tolerability. Only about 50% of individuals infected with HCV genotype 1 achieve sustained virological response when treated with a combination of pegylated interferon ␣ and ribavirin (1, 2). In addition, high viral load, age, body weight, co-infection with human immunodeficiency virus, and cirrhosis negatively affect the probability of achieving sustained virological response (3, 4). Therefore, there is an urgent need to develop new and more effective therapies for the treatment of HCV infection. A number of new antiviral candidates are currently being evaluated in clinical studies, the majority targeting either the HCV protease or HCV polymerase enzymes, which are essential for viral replication (5). The HCV RNA-dependent RNA polymerase, NS5B, contains the active site responsible for viral RNA synthesis and functions as part of a membrane-associated replicase complex. Nucleoside and non-nucleoside inhibitors of HCV polymerase h...

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