Review Article: Specifically Targeted Anti-viral Therapy for Hepatitis C – A New Era in Therapy

C. M. Lange; C. Sarrazin; S. Zeuzem


Aliment Pharmacol Ther. 2010;32(1):14-28. 

In This Article

Compounds Targeting HCV Replication

NS5B Polymerase Inhibitors

NS5B RNA polymerase inhibitors can be divided into two distinct categories. Nucleoside analogue inhibitors (NIs) like valopicitabine (NM283), R7128, R1626, PSI-7851 or IDX184 mimic the natural substrates of the polymerase and are incorporated into the growing RNA chain, thus causing direct chain termination by tackling the active site of NS5B.[29,57–67] As the active centre of NS5B is a highly conserved region of the HCV genome, NIs are potentially effective against different genotypes, in contrast to NS3/4A inhibitors. Moreover, single amino acid substitutions in every position of the active centre may result in loss of function. Thus, there is a relatively high genetic barrier in the development of resistances to NIs.

In contrast to NIs, the heterogeneous class of non-nucleoside inhibitors (NNIs) bind to different allosteric enzyme sites, which results in conformational protein change before the elongation complex is formed.[68] To inhibit NS5B allostericaly, a high chemical affinity of the compound to the enzyme is required. NS5B is structurally organized in a characteristic 'right hand motif', containing finger, palm and thumb domains, and offers at least four NNI-binding sites, a benzimidazole-(thumb 1)-, thiophene-(thumb 2)-, benzothiadiazine-(palm 1)- and benzofuran-(palm 2)-binding site.[68,69] Theoretically, NNIs targeting different binding sites can be used in combination or in sequence to manage the development of resistance. As NNIs bind distantly to the active centre of NS5B, their application results more frequently in resistance development than during treatment with NIs. In addition, mutations at the NNI-binding sites do not necessarily lead to impaired function of the enzyme.

Nucleoside Analogues

Valopicitabine (NM283, 2′-C-methylcytidine/NM107) was the first nucleoside inhibitor investigated in patients with chronic hepatitis C. Anti-viral activity of valopicitabine was low.[70] The clinical development of valopicitabine was stopped because of gastrointestinal side effects and an insufficient risk/benefit profile.

The second nucleoside inhibitor investigated in patients with chronic hepatitis C was R1626 (4′-azidocytidine/PSI-6130). A phase 1 study showed a high anti-viral activity at high doses of R1626 in patients infected with HCV genotype 1.[63–65] No viral breakthrough with selection of resistant variants was reported from monotherapy or combination studies with pegylated interferon ± ribavirin. However, severe lymphopenia and infectious disease adverse events led to the stop of R1626 development.

R7128 is another nucleoside polymerase inhibitor with potent anti-viral activity during monotherapy in HCV genotype 1 patients. Currently, R7128 is investigated in phase 2 clinical trials in HCV genotype 1, 2 and 3 infected patients in combination with pegylated interferon and ribavirin.[59] Both during monotherapy and combination therapy with pegylated interferon and ribavirin, no resistance development against R7128 was observed.

Other nucleoside analogue inhibitors of the NS5B polymerase (PSI-7851 and IDX184) are evaluated in phase 1 clinical trials in patients with chronic hepatitis C and many compounds are under preclinical development.[13] For a summary of anti-viral activities of nucleoside polymerase inhibitors see Figure 7.

Figure 7.

Anti-viral activity of nucleoside analogue NS5B polymerase inhibitors during monotherapy for 3–14 days (modified from [13]).

Non-nucleoside Analogues

NNI-site 1 Inhibitors (Thumb 1/benzimidazole Site). BILB1941, BI207127 and MK-3281 are NNI-site 1 inhibitors which have been investigated in clinical phase 1 trials and exhibit low to medium anti-viral activities.[13,71,72] No selection of resistant variants and viral breakthrough has been observed during 5 days of treatment with BILB1941 or BI207127.

NNI-site 2 Inhibitors (Thumb 2/thiophene Site). Filibuvir (PF-00868554) is a NNI-site 2 inhibitor with medium anti-viral activity in a phase 1 study. In a subsequent trial viral breakthrough was observed in 5 of 26 patients during combination therapy with pegIFN-α 2a and ribavirin for 4 weeks.[72]

Other NNI-site 2 inhibitors which were evaluated in phase 1 trials are VCH-759, VCH-916 and VCH-222, their anti-viral efficacy is shown in Figure 8.[13,73] Like during treatment with filibuvir, VCH-759 and VCH-916 application resulted in viral breakthroughs with selection of resistant variants, indicating a low genetic barrier to resistance of these agents.

Figure 8.

Anti-viral activity of non-nucleoside analogue NS5B polymerase inhibitors during monotherapy for 3–14 days (modified from [13]).

NNI-site 3 Inhibitors (Palm 1/benzothiadiazine Site). ANA598 is a NNI-site 3 inhibitor which displayed anti-viral activity during treatment of HCV genotype 1 infected patients. No viral breakthrough was observed during a short term monotherapy trial.[74]

NNI-site 4 Inhibitors (Palm 2/benzofuran Site). Monotherapy with the NNI-site 4 inhibitor HCV-796 showed low anti-viral activity in HCV genotype 1 infected patients and resulted in selection of resistant variants and viral breakthrough in several patients.[75,76] GS-9190 displays a low anti-viral activity in a clinical study and variants conferring resistance were identified in the beta-hairpin of the polymerase.

An overview of the anti-viral activities of non-nucleoside polymerase inhibitors in monotherapy studies is shown in Figure 8.

NS5A Inhibitors

In a single ascending dose study it was shown that inhibition of the NS5A protein with BMS-790052 leads to a sharp initial decline of HCV RNA concentrations.[77] BMS-790052 binds to domain I of the NS5A protein, which was shown to be important for regulation of HCV replication. No clinical data on resistance to this class of drugs have been presented yet and results of multiple dose and combination therapy studies have to be awaited.

NS4B Inhibitors

NS4B is a hydrophobic protein mandatory for the formation of the membranous web of the HCV replication complex. Moreover, NS4B displays RNA-binding properties which may be crucial in HCV RNA procession and replication. In vitro, inhibition of NS4B by small molecular compounds has been shown to compromise HCV replication significantly.[78]

Combination Therapies of Specific Anti-virals

It is a fundamental question whether SVR can be achieved by combination therapies of different STAT-C compounds without pegIFN-α and ribavirin. A first clinical trial (INFORM-1 study) evaluated the combination of a polymerase inhibitor (R7128) and a NS3 inhibitor (R7227/ITMN191). In this proof-of-principle study, patients were treated with both compounds for up to 2 weeks. HCV RNA concentrations decreased up to 5.2 log10 IU/mL, no viral break-through was observed, and HCV RNA was undetectable at the end of dosing in up to 63% of treatment-naïve patients.[79] Future clinical trials need to address whether a long-term suppression of HCV replication or even SVR can be achieved with such direct anti-viral combination therapies. Currently, combination studies with several compounds are conducted (R7128 + R7227, VX-950 + VCH222, BMS790052 + BMS650032, BI201335 + BI207127).


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