NS5B RNA Dependent RNA Polymerase Inhibitors: The Promising Approach to Treat Hepatitis C Virus Infections

R.R.       Deore; J.-W.       Chern

Abstract

Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of worlds 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.

Keywords: Hepatitis C virus, NS5B polymerase, nucleoside inhibitors, non-nucleoside inhibitors, active site, allosteric site, structure activity relationship, replicon activity, Hepatitis C virus (HCV), ribavirin, pegylated interferon, RNA polymerase, cirrhosis, hepatocellular carcinoma, Inter-nal ribosomal entry site (IRES), putative sub-strate-binding, hydrophilic cavity, pivaloyloxymethyl, Structure ac-tivity relationship (SAR), Flaviviridae, valacyclovir, Miscellaneous Nucleoside Inhibitors, Viramidine, cytidine triphosphate, uridine triphosphate, Benzothiadiazines, Benzimidazoles, Dihydropyrones, Proline Sulfonamides, Anthranilic Acid Derivatives, Indole-N-Acetamides, glucuronida-tion, hydroxyoxadiazole, submicromolar activity, replicon assays, N-benzoylpyrro-lidine, thio-phene, thiazole, Benzoylaminoacrylic Acids, Aminopyrazole, Aminothiazole, Carbazoles, Cyclopenta[b]indoles, tetracyclic compounds, Nonstructural protein 5B, Interferon-α, Pharmacokinetic, S-acetyl-2-thioethyl, Diketo acid, High Throughput Screening