2. Academic Validation
  3. Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage

Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage

  • Eur J Med Chem. 2018 Apr 10:149:45-55. doi: 10.1016/j.ejmech.2018.02.061.
Xin Zhang 1,  Qiang Liu 2,  Na Zhang 1,  Qian-Qian Li 2,  Zhan-Dong Liu 3,  Ying-Hong Li 1,  Li-Mei Gao 1,  You-Chun Wang 2,  Hong-Bin Deng 4,  Dan-Qing Song 5
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 National Institute for the Control of Pharmaceutical and Biological Products, Beijing 100050, China.
  • 3 Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
  • 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].
  • 5 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: 29494844 DOI: 10.1016/j.ejmech.2018.02.061
Abstract

Preventing filoviruses in the entry stage is an attractive Antiviral strategy. Taking aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine Cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.

Keywords

Aloperine; Druglike; EBOV; Filovirus; Structure−activity relationship.

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