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.
- 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].
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.