Identification of N,N-disubstituted phenylalanines as a novel class of inhibitors of hepatitis C NS5B polymerase.
ABSTRACT The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described.
Article: Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research.[show abstract] [hide abstract]
ABSTRACT: Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.Medicinal Research Reviews 08/2012; · 10.70 Impact Factor
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ABSTRACT: The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime target for development of HCV replication inhibitors. Here, we report the identification of a new class of HCV NS5B inhibitors belonging to the coumestan family of phytoestrogens. Based on the in vitro NS5B RNA-dependent RNA polymerase (RdRp) inhibition in the low micromolar range by wedelolactone, a naturally occurring coumestan, we evaluated the anti-NS5B activity of four synthetic coumestan analogues bearing different patterns of substitutions in their A and D rings, and observed a good structure-activity correlation. Kinetic characterization of coumestans revealed a noncompetitive mode of inhibition with respect to nucleoside triphosphate (rNTP) substrate and a mixed mode of inhibition towards the nucleic acid template, with a major competitive component. The modified order of addition experiments with coumestans and nucleic acid substrates affected the potencies of the coumestan inhibitors. Coumestan interference at the step of NS5B-RNA binary complex formation was confirmed by cross-linking experiments. Molecular docking of coumestans within the allosteric site of NS5B yielded significant correlation between their calculated binding energies and IC(50) values. Coumestans thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural refinement and development of potent NS5B inhibitors.Nucleic Acids Research 04/2008; 36(5):1482-96. · 8.03 Impact Factor