GS-7977: a promising nucleotide analog NS5B polymerase inhibitor of HCV

2012 ◽  
Vol 7 (6) ◽  
pp. 537-546 ◽  
Author(s):  
Valérie Martel-Laferrière ◽  
Douglas T Dieterich
Keyword(s):  
Nucleotide Analog ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

scholarly journals Hepatitis C virus treatment advances for thalassaemia patients

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
George Papatheodoridis
Keyword(s):  
Liver Disease ◽  
Protease Inhibitor ◽  
Blood Transfusions ◽  
Hcv Treatment ◽  
Once Daily ◽  
Ns5a Inhibitor ◽  
Nucleotide Analogue ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

Chronic infection with hepatitis C virus (HCV) is a major problem for thalassaemia patients, as blood transfusions before 1990 were associated with a high risk of HCV infection. Given the high prevalence of co-morbidities, thalassaemia patients are at an increased risk for dying from end-stage liver disease or hepatocellular carcinoma. HCV treatment in thalassaemia patients was challenging in the interferon-alfa (IFN) era not only due to its unfavourable safety and tolerability profile but due to necessary combined use of ribavirin (RBV) and the subsequent haemolysis and increased need for blood transfusions. The introduction of the current direct acting antivirals (DAAs), which can be used in IFNfree and RBV-free regimens, has dramatically improved the management of all HCV patients including those with thalassaemia. Currently, depending on HCV genotype and availability in each country, the main available DAAs combinations are the co-formulation of sofosbuvir with ledipasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/90 mg once daily),, the co-formulation of paritaprevir boosted by ritonavir with ombitasvir (NS3/4 protease inhibitor/ritonavir/NS5A inhibitor, two tablets of 75/50/12.5 mg once daily) perhaps with addition of dasabuvir (non-nucleos(t)ide analogue NS5B polymerase inhibitor, one tablet of 250 mg twice daily), the co-formulation of grazoprevir with elbasvir (NS3/4 protease inhibitor/NS5A inhibitor, one tablet of 100/50 mg once daily) and the co-formulation of sofosbuvir with velpatasvir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor, one tablet of 400/100 mg once daily). In 2017, the co-formulation of glecaprevir with pibrentasvir (NS3/4 protease inhibitor/NS5A inhibitor, three tablets of 100/40 mg once daily) and the co-formulation of sofosbuvir with velpatasvir and voxilaprevir (nucleotide analogue NS5B polymerase inhibitor/NS5A inhibitor/ NS3/4 protease inhibitor, one tablet of 400/100/100 mg once daily) were also approved and started to be used in some countries. According to all international current guidelines, thalassaemia patients do not represent a special group for the current HCV treatment and can be treated with the same indications and regimens used for patients without haemoglobinopathies. However, in countries which still prioritize the use of DAAs according to the severity of liver disease, thalassaemia patients are often excluded from such prioritization and have access to DAAs therapy regardless of their fibrosis severity. Moreover, all guidelines recommend that thalassaemia patients should be preferentially treated not only with IFN-free but RBV-free DAAs regimens too. In a proper clinical trial, only a 12-week regimen of grazoprevir/ elbasvir has been evaluated and proven to be highly efficacious and well tolerated among patients with inherited blood disorders and HCV genotype 1 or 4 infection. In addition, different DAAs regimens have been reported to be safe and effective for the treatment of HCV thalassaemia patiens in clinical practice. Given the availability of the current effective and safe DAAs and the frequent follow-up of thalassaemia patients in a few specific units, such patients could be a targeted population for “HCV micro-elimination” on the road towards the global HCV elimination in each country.

scholarly journals In VitroAntiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir

2016 ◽  
Vol 60 (3) ◽  
pp. 1847-1853 ◽  
Author(s):  
Guofeng Cheng ◽  
Yang Tian ◽  
Brian Doehle ◽  
Betty Peng ◽  
Amoreena Corsa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Fixed Dose ◽  
Resistance Profile ◽  
Direct Acting Antiviral ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase

Ledipasvir (LDV; GS-5885), a component of Harvoni (a fixed-dose combination of LDV with sofosbuvir [SOF]), is approved to treat chronic hepatitis C virus (HCV) infection. Here, we report key preclinical antiviral properties of LDV, includingin vitropotency,in vitroresistance profile, and activity in combination with other anti-HCV agents. LDV has picomolar antiviral activity against genotype 1a and genotype 1b replicons with 50% effective concentration (EC50) values of 0.031 nM and 0.004 nM, respectively. LDV is also active against HCV genotypes 4a, 4d, 5a, and 6a with EC50values of 0.11 to 1.1 nM. LDV has relatively lessin vitroantiviral activity against genotypes 2a, 2b, 3a, and 6e, with EC50values of 16 to 530 nM.In vitroresistance selection with LDV identified the single Y93H and Q30E resistance-associated variants (RAVs) in the NS5A gene; these RAVs were also observed in patients after a 3-day monotherapy treatment.In vitroantiviral combination studies indicate that LDV has additive to moderately synergistic antiviral activity when combined with other classes of HCV direct-acting antiviral (DAA) agents, including NS3/4A protease inhibitors and the nucleotide NS5B polymerase inhibitor SOF. Furthermore, LDV is active against known NS3 protease and NS5B polymerase inhibitor RAVs with EC50values equivalent to those for the wild type.

The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor

2018 ◽  
Vol 22 (10) ◽  
pp. 1393-1408 ◽  
Author(s):  
Jeffrey Bien ◽  
Akin Davulcu ◽  
Albert J. DelMonte ◽  
Kenneth J. Fraunhoffer ◽  
Zhinong Gao ◽  
...  
Keyword(s):  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

Formal Synthesis of Hepatitis C Virus NS5B Polymerase Inhibitor

Synlett ◽  
2013 ◽  
Vol 24 (16) ◽  
pp. 2143-2147 ◽  
Author(s):  
Hidetoshi Tokuyama ◽  
Takahiro Noro ◽  
Kentaro Okano
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Formal Synthesis ◽  
Ns5b Polymerase Inhibitor ◽  
Polymerase Inhibitor ◽  
Ns5b Polymerase
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