2. Academic Validation
  3. Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism

Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism

  • Eur J Med Chem. 2018 Jan 1;143:1053-1065. doi: 10.1016/j.ejmech.2017.12.002.
Xin Zhang 1,  Xiao-Qin Lv 1,  Sheng Tang 1,  Lin Mei 2,  Ying-Hong Li 1,  Jing-Pu Zhang 1,  Jian-Dong Jiang 1,  Zong-Gen Peng 3,  Dan-Qing Song 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Qingdao Municipal Hospital, Qingdao 266011, China.
  • 3 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 29232582 DOI: 10.1016/j.ejmech.2017.12.002
Abstract

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.

Keywords

Aloperine; Druglike; HCV; Host components; Structure−activity relationship.

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