NS5B RNA Dependent RNA Polymerase Inhibitors: The Promising Approach to Treat Hepatitis C Virus Infections
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.
Keywords: Aminopyrazole; Aminothiazole; Anthranilic Acid Derivatives; Benzimidazoles; Benzothiadiazines; Benzoylaminoacrylic Acids; Carbazoles; Cyclopenta[b]indoles; Dihydropyrones; Diketo acid; Flaviviridae; Hepatitis C virus; Hepatitis C virus (HCV); High Throughput Screening; Indole-N-Acetamides; Inter-nal ribosomal entry site (IRES); Interferon-α; Miscellaneous Nucleoside Inhibitors; N-benzoylpyrro-lidine; NS5B polymerase; Nonstructural protein 5B; Pharmacokinetic; Proline Sulfonamides; RNA polymerase; S-acetyl-2-thioethyl; Structure ac-tivity relationship (SAR); Viramidine; active site; allosteric site; cirrhosis; cytidine triphosphate; glucuronida-tion; hepatocellular carcinoma; hydrophilic cavity; hydroxyoxadiazole; non-nucleoside inhibitors; nucleoside inhibitors; pegylated interferon; pivaloyloxymethyl; putative sub-strate-binding; replicon activity; replicon assays; ribavirin; structure activity relationship; submicromolar activity; tetracyclic compounds; thiazole; thio-phene; uridine triphosphate; valacyclovir
Document Type: Research Article
Publication date: November 1, 2010
- Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.