期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 143, 期 -, 页码 1053-1065出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.12.002
关键词
Aloperine; HCV; Structure-activity relationship; Host components; Druglike
资金
- National Natural Science Foundation of China [21472246, 81321004, 81322050]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-3-012]
Aloperine (1), a Chinese natural product with a unique endocyclic scaffold, was first identified to be a potent hepatitis C virus (HCV) inhibitor in our laboratory. Thirty-four new aloperine derivatives were designed, synthesized and evaluated for their anti-HCV activities taking 1 as the lead. Among them, compound 7f exhibited the potential potency with EC50 values in a micromolar range against both wild type and direct-acting antiviral agents (DAAs)-resistant variants, and synergistically inhibited HCV replication with approved DAAs. Furthermore, it also owned a good oral pharmacokinetic and safety profile, suggesting a highly druglike nature. The primary mechanism showed that 7f might target host components, distinctly different from the DAAs currently used in clinic. Therefore, we consider aloperine derivatives to be a novel class of anti-HCV agents, and compound 7f has been selected as a promising antiviral candidate for further investigation. (C) 2017 Elsevier Masson SAS. All rights reserved.
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