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NS5B

About: NS5B is a research topic. Over the lifetime, 1314 publications have been published within this topic receiving 59534 citations.


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Journal ArticleDOI
TL;DR: This review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.
Abstract: Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti-HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ≈50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity.

40 citations

Journal ArticleDOI
TL;DR: Strains of HCV genotype 6a isolated from patients can be adapted to propagate in cultured cells, permitting studies of the complete life cycle for this important genotype, which quickly becomes resistant to single inhibitors via the rapid emergence and persistence of RAS.

40 citations

Journal ArticleDOI
TL;DR: The in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.
Abstract: As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC50], 0.048 to 0.68 μM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC50, 1.5 μM). The active 5′-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with Ki/Km values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1′-CN and 2′-C-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance in vitro. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its in vitro profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.

39 citations

Journal ArticleDOI
TL;DR: These data aid in the classification of uncommon HCV subtypes while also providing a high-resolution view of viral diversity within infected patients, which may be relevant to the development of therapeutic regimens to minimize drug resistance.
Abstract: Hepatitis C virus (HCV) is an enveloped, positive-strand RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. Seven confirmed genotypes (1–7) are generally distinguished by phylogenetic methods and pair-wise distance calculations [1, 2]. On the basis of full genome nucleotide sequences, HCV genotypes diverged from each other by a pair-wise distance of >30%. Individual genotypes can be further divided into more closely related subtypes that diverged by a pair-wise distance of 15%–30%. All viral genotypes retain their repertoire of colinear structural and nonstructural genes, thereby facilitating preliminary genotype classification on the basis of partial genome sequences of short fragments (approximately 300–400 nucleotides) in the structural core/E1 region and the nonstructural NS5B region [3]. However, full genome sequences remain indispensible for the detection of genome recombination events. While only recombinant HCV genotype 2 k/1b viruses have been found to actively circulate in the population so far [4–7], recombinants of genotypes 2/5, 2b/1b, 2b/1a, and 2i/6p have been detected in single isolates from humans [8–11]. Furthermore, the frequency of HCV intergenotype and intragenotype recombination may be underestimated because of the lack of robust detection methods [12, 13]. Although genotyping based on core/E1 or NS5B sequences has resulted in the provisional classification of a large number of subtype variants within each genotype, at least 1 but preferably ≥2 full genome sequences are required to confirm subtype designation [2, 12]. Accurate genotype and subtype classification is clinically important because major genotypes differ considerably in their response rates to treatment with pegylated interferon and ribavirin and with directly acting antiviral drugs (DAAs) that are designed mainly against genotype 1 isolates. The limited efficacy of DAAs against other genotypes has been shown for genotype 3 [14], and treatment response rates for drug regimens containing boceprevir (an NS3 protease inhibitor) or BMS-790052 (an NS5A inhibitor) were found to vary even between subtypes 1a and 1b [15, 16]. Different baseline frequencies of drug resistance mutations may account for these differences [17], and such variation might become more significant if interferon-free regimens containing 1 or more DAAs could indeed displace the current standard of care [18]. Until clinically tolerable DAAs with high barriers to resistance against the complete spectrum of HCV genotypes become available [18, 19], accurate subtype determination and, possibly, drug resistance profiling of the individual's viral population may guide the optimal choice of drugs. Full genome deep sequencing, as performed in this study, allows the identification of drug resistance mutations across the genome that may exist as dominant or minor variants in treatment-naive patients, thereby informing the design of therapeutic regimens.

39 citations

Posted ContentDOI
16 Jun 2020-bioRxiv
TL;DR: Both drugs inhibited independent events during RNA synthesis and this was particularly the case for DCV, which also targeted secondary RNA structures in the SARS-CoV-2 genome, which provide a basis to further explore these agents as COVID-19 antiviral candidates.
Abstract: The infection by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes major public health concern and economic burden. Although clinically approved drugs have been repurposed to treat individuals with 2019 Coronavirus disease (COVID-19), the lack of safety studies and limited efficiency as well jeopardize clinical benefits. Daclatasvir and sofosbuvir (SFV) are clinically approved direct-acting antivirals (DAA) against hepatitis C virus (HCV), with satisfactory safety profile. In the HCV replicative cycle, daclatasvir and SFV target the viral enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV and SARS-CoV-2 motivated us to further study the activity of daclatasvir and SFV against the new coronavirus. Daclatasvir consistently inhibited the production of infectious SARS-CoV-2 virus particles in Vero cells, in the hepatoma cell line HuH-7 and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 μM, respectively. Daclatasvir targeted early events during SARS-CoV-2 replication cycle and prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection. Sofosbuvir, although inactive in Vero cells, displayed EC50 values of 6.2 and 9.5 μM in HuH-7 and Calu-3 cells, respectively. Our data point to additional antiviral candidates, in especial daclatasvir, among drugs overlooked for COVID-19, that could immediately enter clinical trials.

39 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202310
202258
202128
202033
201943
201842