Details

Autor(en) / Beteiligte

• Kim, Hee Sun
• You, Youngsu
• Mun, Jaegon
• Gadhe, Changdev G.
• Moon, Heejo
• Lee, Jae Seung
• Pae, Ae Nim
• Kohara, Michinori
• Keum, Gyochang
• Kim, Byeong Moon
• Jang, Sung Key

Titel

Structure-activity relationships of fluorene compounds inhibiting HCV variants

Ist Teil von

• Antiviral research, 2020-02, Vol.174, p.104678-104678, Article 104678

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase that cleaves the HCV polyprotein into various functional proteins, RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens due to the high efficacy and low toxicity of drugs targeting NS5A. Here we report fluorene compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method. [Display omitted] ●We report a new series of NS5A inhibitors containing a fluorene proline-amide skeleton.●Efficacy of the compounds on RAVs L31V gradually increased as the length of alkyl chain increased.●Substitutions of proline (Y and Z) improved the efficacies of compounds against RAVs Y93H and L31V+Y93H.●The structure-activity relationships (SARs) between the inhibitors and the RAVs were analyzed.