New NS5B polymerase inhibitors for hepatitis C

Abravanel, Florence; Nicot, Florence; Izopet, Jacques

doi:10.1517/13543784.2010.500285

Cited by 79 publications

(45 citation statements)

References 74 publications

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“…Furthermore, several modified nucleoside analogs and nonnucleoside inhibitors with potent inhibitory activities against NS5B have been reported as potential therapeutics for HCV (for a review, see reference 19). The majority of nucleoside analogs active against HCV can be divided into two classes: compounds harboring 2Ј modifications (e.g., NM-107 and PSI-6130) or those harboring 4Ј modifications (e.g., R-1479) of the ribose ring.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

Berke¹,

Vijgen²,

Lachau‐Durand³

et al. 2011

Antimicrob Agents Chemother

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Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed in vitro and in vivo suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the in vitro inhibitory activity and mode of action of 2-deoxy-2-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain. In vitro combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes in vitro. TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising in vitro virology and biology profile.Infection with hepatitis C virus (HCV), the causative agent of hepatitis C, is an important global health burden, with an estimated 120 to 170 million persons chronically infected (7,11). Chronic HCV infection can lead to liver cirrhosis and hepatocellular carcinoma and is the leading cause of liver transplantation (10). The virus is transmitted mainly via bloodblood contact, and spontaneous virus clearance has been estimated to be achieved for 26% of infected subjects (29).HCV is a member of the Flaviviridae family of viruses in the genus Hepacivirus, comprising at least six major genotypes and multiple subtypes. The 9.6-kb positive-sense, single-stranded RNA genome of HCV encodes four structural proteins (the core protein, the envelope glycoproteins E1 and E2, and p7) and six nonstructural proteins responsible for viral replication (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The nonstructural protein NS5B is an RNA-dependent RNA polymerase (RdRp) responsible for the amplification of the HCV RNA and the assembly of the replicase complex at the endoplasmic reticulum membrane (3, 25).Currently, HCV patients are treated with a combination of weekly pegylated alpha interferon (IFN-␣) injections and twice-daily ribavirin, which has considerable tolerability issues (28) and results in a sustained viral response in only 40 to 50% of patient...

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Section: Discussionmentioning

confidence: 99%

Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

Berke¹,

Vijgen²,

Lachau‐Durand³

et al. 2011

Antimicrob Agents Chemother

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“…Clinical proof of concept has been achieved for a number of DAAs targeting some of these proteins, including the serine protease activity of NS3 (11,16,25,31,32,45,53) and the RNA-dependent RNA polymerase activity of NS5B (20,26,46; H. Tatum et al, poster 1163, presented at the 47th European Association for the Study of the Liver [EASL] Congress, Barcelona, Spain, 18 to 22 April 2011). More recently, daclatasvir (DCV) ( Table 1) was the first NS5A replication complex inhibitor to show proof of concept in the clinic, demonstrating in early clinical testing the potential for this class of inhibitor to become a valuable component of an all-oral treatment regimen for HCV (15).…”

mentioning

confidence: 99%

“…Resistance mutations have been identified both in vitro and in vivo upon treatment with nearly all inhibitors of HCV serine protease, NS5A, or allo-steric RNA polymerase inhibitors advanced to date (3,19,22,23,24,30,36,38,51,52,57,60,62), with good correlation observed between resistance emergence in the replicon system and in vivo. Recent literature indicates that treatment with combinations of non-cross-resistant inhibitors not only improves antiviral activity during treatment but also suppresses the posttreatment viral rebound often associated with monotherapy (19,21,26). To achieve a sustained viral response (SVR), it would be essential to use combination therapies similar to those that have recently been explored in replicon studies (5,10,29), animal models (44), and patient studies (14,51) as a viable approach to improving the efficacy, tolerability, and compliance issues associated with current therapies.…”

mentioning

confidence: 99%

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Pelosi

Voss

Liu

et al. 2012

Antimicrob Agents Chemother

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Three hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additivesynergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic. H epatitis C virus (HCV) is a positive-stranded RNA virus in theFlaviviridae family of enveloped virions which affects an estimated 170 million people worldwide and is the major cause of chronic hepatitis. Currently, approximately 50% of patients infected with genotype 1 (gt 1), the most prevalent form of the virus, fail to achieve a sustained reduction in viral load with therapy employing pegylated alpha interferon (IFN-␣) plus ribavirin (alfa/RBV) (52,54,56). A substantial fraction (20%) of chronically infected patients develop serious progressive liver disease, including cirrhosis or hepatocellular carcinoma. alfa/RBV treatment is associated with a high incidence (Ͼ30%) of adverse effects, some of which are of sufficient severity to cause patients to discontinue therapy (56). Despite the recent approval of two new direct-acting antiviral agents (DAAs), boceprevir and telaprevir, for use in combination with alfa/RBV (18, 47), their use may be limited by poor efficacy in some patient populations, inconvenient 3-times-daily dosing of the DAA, and association with side effects, including anemia, rash, and gastrointestinal effects, in addition to the well-documented spectrum of adverse effects associated with alfa/RBV. Although addition of these DAAs to the standard of care for HCV represents a significant i...

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“…There is evidence that the selection of resistant variants and virus breakthrough is more frequent in patients infected with subtype 1b than in those harboring subtype 1a (13,25,40). The antiviral activities of nucleoside analogs of polymerase inhibitors are similar regardless of the HCV subtype, while nonnucleoside inhibitors are more active against subtype 1b than against subtype 1a (18,31,41). These findings suggest that the antiviral activity of new anti-HCV agents may also vary with the subtypes of genotypes other than 1.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Genotyping Using an Oligonucleotide Microarray Based on the NS5B Sequence

et al. 2010

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The genotype of the hepatitis C virus (HCV) is essential for determining treatment duration in clinical practice and for epidemiological and clinical studies. Currently, few genotyping assays that determine the HCV subtype are available. This report describes a microarray-based molecular technique for identifying the HCV genotype and subtype. It uses low-density hydrogel-based biochips containing genotype-and subtype-specific oligonucleotides based on the sequences of the NS5B region of the HCV genome. The biochip contains 120 oligonucleotides that identify genotypes 1 to 6 and 36 (1a, 1b, 1c, 1d, 1e, 2a, 2b, 2c, 2d, 2i, 2j, 2k, 2l, 2m, 3a, 3b, 3k, 4a, 4c, 4d, 4f, 4h, 4i, 4k, 4n, 4o, 4p, 4r, 4t, 5a, 6a, 6b, 6d, 6g, 6h, and 6k) subtypes. The procedure included amplification of a 380-nucleotide (nt) fragment of NS5B and its hybridization on the biochip. Tests on 345 HCV-positive samples showed that the assay agreed with NS5B sequencing 100% for the genotype and 99.7% for the subtype. The hybridization on the microarray and the NS5B sequence were in 100% agreement for identifying the most common subtypes, 1a, 1b, 4a, 4d, and 3a. This approach is a promising tool for HCV genotyping, especially for implementing the new anti-HCV drugs that require accurate identification of clinically relevant subtypes.

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New NS5B polymerase inhibitors for hepatitis C

Abstract: NS5B polymerase inhibitors will form an integral part of more effective anti-HCV therapy, in combination with interferon or with other directly acting antiviral agents.

Cited by 79 publications

References 74 publications

Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

Hepatitis C Virus Genotyping Using an Oligonucleotide Microarray Based on the NS5B Sequence

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