Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage
| Autor: | Hongbin Deng, Li–Mei Gao, Dan–Qing Song, You–Chun Wang, Ying–Hong Li, Zhan Dong Liu, Liu Qiang, Xin Zhang, Qian–Qian Li, Na Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Quinolizidines Pharmacology medicine.disease_cause Chlorobenzenes Antiviral Agents Virus Cathepsin B Marburg virus 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Piperidines Viral entry Drug Discovery medicine Potency Humans Ebola virus Chemistry Organic Chemistry Late stage General Medicine Virus Internalization Filoviridae 030104 developmental biology Cathepsin B activity 030220 oncology & carcinogenesis Cysteine |
| Zdroj: | European journal of medicinal chemistry. 149 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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