scholarly journals Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors

2021 ◽  
Vol 14 (4) ◽  
pp. 292
Author(s):  
Mai H. A. Mousa ◽  
Nermin S. Ahmed ◽  
Kai Schwedtmann ◽  
Efseveia Frakolaki ◽  
Niki Vassilaki ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Inhibitory Activity ◽  
Antiviral Effect ◽  
Optimized Design ◽  
Amino Acid Residues ◽  
Design And Synthesis ◽  
Carbamate Group ◽  
Direct Acting ◽  
Alkyl Carbamate

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.

scholarly journals Cross-Genotypic Examination of Hepatitis C Virus Polymerase Inhibitors Reveals a Novel Mechanism of Action for Thumb Binders

2014 ◽  
Vol 58 (12) ◽  
pp. 7215-7224 ◽  
Author(s):  
Auda A. Eltahla ◽  
Enoch Tay ◽  
Mark W. Douglas ◽  
Peter A. White
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
De Novo ◽  
Hcv Rna ◽  
Amino Acid Residues ◽  
Recombinant Enzymes ◽  
Polymerase Inhibitors ◽  
Binding Pockets ◽  
Direct Acting

ABSTRACTDirect-acting antivirals (DAAs) targeting proteins encoded by the hepatitis C virus (HCV) genome have great potential for the treatment of HCV infections. However, the efficacy of DAAs designed to target genotype 1 (G1) HCV against non-G1 viruses has not been characterized fully. In this study, we investigated the inhibitory activities of nonnucleoside inhibitors (NNIs) against the HCV RNA-dependent RNA polymerase (RdRp). We examined the ability of six NNIs to inhibit G1b, G2a, and G3a subgenomic replicons in cell culture, as well asin vitrotranscription by G1b and G3a recombinant RdRps. Of the six G1 NNIs, only the palm II binder nesbuvir demonstrated activity against G1, G2, and G3 HCV, in both replicon and recombinant enzyme models. The thumb I binder JTK-109 also inhibited G1b and G3a replicons and recombinant enzymes but was 41-fold less active against the G2a replicon. The four other NNIs, which included a palm I binder (setrobuvir), two thumb II binders (lomibuvir and filibuvir), and a palm β-hairpin binder (tegobuvir), all showed at least 40-fold decreases in potency against G2a and G3a replicons and the G3a enzyme. This antiviral resistance was largely conferred by naturally occurring amino acid residues in the G2a and G3a RdRps that are associated with G1 resistance. Lomibuvir and filibuvir (thumb II binders) inhibited primer-dependent but notde novoactivity of the G1b polymerase. Surprisingly, these compounds instead specifically enhanced thede novoactivity at concentrations of ≥100 nM. These findings highlight a potential differential mode of RdRp inhibition for HCV NNIs, depending on their prospective binding pockets, and also demonstrate a surprising enhancement ofde novoactivity for thumb RdRp binders. These results also provide a better understanding of the antiviral coverage for these polymerase inhibitors, which will likely be used in future combinational interferon-free therapies.

Evaluation of antiviral effect of type I, II, and III interferons on direct-acting antiviral-resistant hepatitis C virus

2017 ◽  
Vol 146 ◽  
pp. 130-138 ◽  
Author(s):  
Atsushi Hamana ◽  
Yuki Takahashi ◽  
Takuro Uchida ◽  
Makiya Nishikawa ◽  
Michio Imamura ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Effect ◽  
Type I ◽  
Direct Acting Antiviral ◽  
Direct Acting

New Epidemiologic Data Regarding Hepatitis C Virus Infection in Romania

2017 ◽  
Vol 26 (4) ◽  
pp. 381-386
Author(s):  
Mircea Manuc ◽  
Carmen M. Preda ◽  
Corneliu P. Popescu ◽  
Cristian Baicuș ◽  
Theodor Voiosu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Users ◽  
Antiviral Agent ◽  
Virologic Response ◽  
Advanced Fibrosis ◽  
Direct Acting Antiviral ◽  
Genotype 1B ◽  
Direct Acting ◽  
End Stage

Background & Aims: Literature data suggest that HCV genotype-1b is present in 93-99% of the Romanian patients infected with hepatitis C virus (HCV). We present the genotyping tests recently performed on patients with HCV and advanced fibrosis eligible for the Direct-Acting Antiviral (DAA) therapy, as well as the prevalence of these cases across Romania.Methods: The genotyping method was performed on 7,421 HCV patients with advanced fibrosis. The detection method was automatic real time PCR platform M2000 (Abbott). Every subject was introduced into a database including age, sex, county and address.Results: Genotype 1b was almost exclusively present: 7,392/7,421 (99.6%). Genotype 1b patients were 19.6% from Bucharest, 49% were males, with a median age of 60 years. Genotype non-1b was encountered in 29/7,421 subjects (0.4%), 62% were males, 69% from Bucharest and the median age was 52 years. Most of the subjects (75%) were in the 6th and 7th age decade. The prevalence of these cases varied significantly across Romanian counties: the highest was in Bucharest (61.3/105), Bihor (47/105), Iasi (46/105) and Constanța (43/105), and the lowest in Ilfov (2.8/105), Harghita (3.7/105), Covasna (5.4/105) and Maramureș (8.8/105) (p<0.001).Conclusions: Genotype 1b is encountered in 99.6% of patients with chronic hepatitis C and advanced fibrosis from Romania. The presence of genotypes non-1b is more common in Bucharest, in males and at a younger age. There are significant differences regarding the distribution of these cases across Romania: the highest rates are in Bucharest, Bihor, Iasi and Constanta.Abbreviations: BMI: body mass index; DAA: direct-acting antiviral agent; GT: genotype; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; IDU: intravenous drug users; MELD: model for end stage liver disease; NASH: non-alcoholic steatohepatitis; SVR; sustained virologic response.

Efficacy of Direct-Acting Antiviral Combination Therapy in the Treat-ment of Hepatitis C Virus Among Kidney Transplant Patients

2020 ◽  
Vol 18 ◽  
Author(s):  
Mohammed Al Atbee ◽  
Saad Shaheen Al-Taher ◽  
Majid Alabbood
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Kidney Transplant ◽  
Virological Response ◽  
Hepatitis C Virus Infection ◽  
Direct Acting Antiviral ◽  
Transplant Patients ◽  
Kidney Transplant Patients ◽  
Direct Acting

Background: Up to date, there is no consensus on the best combination of direct-acting antiviral to treat hepatitis C virus in kidney transplant recipients. Objective: This study aims to analyze the efficacy of combination of sofosbuvir and ledipasvir regimen for treatment of hepatitis C virus infected kidney transplant patients. Method: A cross-sectional study conducted in a nephrology clinic and the Nephrology Center in Basrah Teaching Hospital from June 2015 to June 2018. Ledifos (90 mg Ledipasvir and 400 mg Sofosbuvir fixed-dose) was given as a single daily dose for all the participants for 12 weeks. Response for therapy was tested by follow up hepatitis C virus load at the end of 12 weeks and 24 weeks. The sustained virological response was defined as negative viral load of hepatitis C virus (aviremia) at the end of therapy. This study was done according to the Helsinki Congress. Results: A total of 60 (16 females) patients with renal transplantation and hepatitis C virus infection were included. Mean age was 40±6.2 years. A sustained virological response observed in all of the patients who received Ledifos after 12 and 24 weeks of therapy for all genotypes (1a, 1b and 4); p= 0.0001. Genotype 1a was more prevalent among males, 34 (56.6%); p= 0.0001, and it was the most common genotype tested negative serologically, 11 (18.3%). Conclusion: Ledifos therapy is effective and safe option for the treatment of hepatitis C virus infection in the post–renal transplant setting.

scholarly journals Real-World Outcomes of Direct-Acting Antiviral Treatment and Retreatment in United Kingdom–Based Patients Infected With Hepatitis C Virus Genotypes/Subtypes Endemic in Africa

2021 ◽  
Author(s):  
Elihu Aranday-Cortes ◽  
C Patrick McClure ◽  
Christopher Davis ◽  
William L Irving ◽  
Kazeem Adeboyejo ◽  
...  
Keyword(s):  
United Kingdom ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Treatment Failure ◽  
Antiviral Treatment ◽  
Natural Resistance ◽  
Eastern Africa ◽  
Middle Income ◽  
Hcv Genotypes ◽  
Direct Acting

Abstract Background Chronic hepatitis C virus (HCV) infection affects 71 million individuals, mostly residing in low- and middle-income countries (LMICs). Direct-acting antivirals (DAAs) give high rates of sustained virological response (SVR) in high-income countries where a restricted range of HCV genotypes/subtypes circulate. Methods We studied United Kingdom–resident patients born in Africa to examine DAA effectiveness in LMICs where there is far greater breadth of HCV genotypes/subtypes. Viral genome sequences were determined from 233 patients. Results Full-length viral genomic sequences for 26 known subtypes and 5 previously unidentified isolates covering 5 HCV genotypes were determined. From 149 patients who received DAA treatment/retreatment, the overall SVR was 93%. Treatment failure was associated primarily with 2 subtypes, gt1l and gt4r, using sofosbuvir/ledipasvir. These subtypes contain natural resistance-associated variants that likely contribute to poor efficacy with this drug combination. Treatment failure was also significantly associated with hepatocellular carcinoma. Conclusions DAA combinations give high SVR rates despite the high HCV diversity across the African continent except for subtypes gt1l and gt4r, which respond poorly to sofosbuvir/ledipasvir. These subtypes are widely distributed across Western, Central, and Eastern Africa. Thus, in circumstances where accurate genotyping is absent, ledipasvir and its generic compounds should not be considered as a recommended treatment option.

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