Ursolic acid derivatives are potent inhibitors against porcine reproductive and respiratory syndrome virus
| Autor: | Yang Chen, Heng Wang, Gaopeng Song, Hui Li, Yarou Gao, Jianxin Chen, Weisan Chen, Wu Li, Dan Xu, Mingxin Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
biology 030306 microbiology animal diseases viruses General Chemical Engineering virus diseases General Chemistry respiratory system Porcine reproductive and respiratory syndrome virus biology.organism_classification Virology Virus Release In vitro 03 medical and health sciences chemistry.chemical_compound Ursolic acid chemistry Viral life cycle In vivo Viral entry Cytotoxicity 030304 developmental biology |
| Zdroj: | RSC Advances. 10:22783-22796 |
| ISSN: | 2046-2069 |
| DOI: | 10.1039/d0ra04070c |
| Popis: | Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Therefore, there is an urgent need to develop new antiviral strategies to prevent PRRSV pandemics. In this study, we showed that 3-O-β-chacotriosyl ursolic acid (1) and its ester analogs possessed anti-PRRSV activity in vitro, of which bioisosteric surrogates 7–15 were further generated with the aim of enhancing the selective index. Our results showed that amidation of the 17-COOH group of UA could significantly reduce cytotoxicity and enhance anti-PRRSV activity in MARC-145 cells. Among them, compound 9 displayed the strongest anti-PRRSV activity with the least cytotoxicity. Potent inhibition of representative compounds 9 and 12 on PRRSV infection was observed not only in MARC-145 cells, but also in primary porcine alveolar macrophages, PRRSV-target cells in vivo. Furthermore, compounds 8, 9, 12 and 14 exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV NADC30-like and GD-XH strains as well as classical CH-1a and VR2332 strains. Mechanistically, compounds 9 and 12 inhibited PRRSV replication by directly inactivating virions and therefore affecting all tested stages of the virus life cycle, including viral entry, replication and progeny virus release, but did not affect cellular susceptibility to PRRSV. Our findings suggest that compound 9 could be a hit PRRSV inhibitor and deserves further in vivo studies in swine. |
| Databáze: | OpenAIRE |
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