Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect
By M. Gao, R. Nettles, M. Belema, L. Snyder, V. Nguyen, R. Fridell, Michael H. Serrano-Wu, D. Langley, Jin‐Hua Sun, Donald R. O’Boyle II and 8 more. Nature, 2010
964 citations recorded by the source corpus.
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
Subfields: Hepatology, Molecular Biology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/c18f96b4b27d46299e44c6b1c1b1511f6a5f74c5
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Citations in the corpus
- Impact of high-throughput screening in biomedical research (2011, methodology): “This approach was used to discover compounds that inhibited hepatitis C virus replication and, after consequent optimization, the approach yielded efficacious clinical candidates with a broad genotype coverag”
- A perspective on multi-target drug discovery and design for complex diseases (2018, background): “Despite the high effectiveness, several combination therapies have been approved since January 2016 because drug-resistance is an already established phenomenon [10].”
- A Quantitative High-Resolution Genetic Profile Rapidly Identifies Sequence Determinants of Hepatitis C Viral Fitness and Drug Sensitivity (2014, background): “It possesses a potent antiviral activity in cell culture, with a half maximal effective concentration (EC50) in the pico molar (pM) range and a cytotoxic concentration in the micro molar (uM) range, yielding a large potential therapeutic window [20].”