- 作者: Shin-Ru Shih, Tzu-Yun Chu, Gadarla Randheer Reddy, Sung-Nain Tseng, Hsiun-Ling Chen, Wen-Fang Tang, Ming-sian Wu, Jiann-Yih Yeh, Yu-Sheng Chao, John T-A Hsu, Hsing-Pang Hsieh, Jim-Tong Horng
- 作者服務機構: Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan333, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background
Influenza viruses are a major cause of morbidity and mortality around the world. More recently,
a swine-origin influenza A (H1N1) virus that is spreading via human-to-human transmission
has become a serious public concern. Although vaccination is the primary strategy for
preventing infections, influenza antiviral drugs play an important role in a comprehensive
approach to controlling illness and transmission. In addition, a search for influenza-inhibiting
drugs is particularly important in the face of high rate of emergence of influenza strains
resistant to several existing influenza antivirals.
Methods
We searched for novel anti-influenza inhibitors using a cell-based neutralization (inhibition of
virus-induced cytopathic effect) assay. After screening 20,800 randomly selected compounds
from a library from ChemDiv, Inc., we found that BPR1P0034 has sub-micromolar antiviral
activity. The compound was resynthesized in five steps by conventional chemical techniques.
Lead optimization and a structure–activity analysis were used to improve potency. Time-ofaddition
assay was performed to target an event in the virus life cycle.
Results
The 50% effective inhibitory concentration (IC50) of BPR1P0034 was 0.42 ± 0.11 μM, when
measured with a plaque reduction assay. Viral protein and RNA synthesis of A/WSN/33
(H1N1) was inhibited by BPR1P0034 and the virus-induced cytopathic effects were thus
significantly reduced. BPR1P0034 exhibited broad inhibition spectrum for influenza viruses but showed no antiviral effect for enteroviruses and echovirus 9. In a time-of-addition assay, in
which the compound was added at different stages along the viral replication cycle (such as at
adsorption or after adsorption), its antiviral activity was more efficient in cells treated with the
test compound between 0 and 2 h, right after viral infection, implying that an early step of viral
replication might be the target of the compound. These results suggest that BPR1P0034 targets
the virus during viral uncoating or viral RNA importation into the nucleus.
Conclusions
To the best of our knowledge, BPR1P0034 is the first pyrazole-based anti-influenza compound
ever identified and characterized from high throughput screening to show potent (sub-μM)
antiviral activity. We conclude that BPR1P0034 has potential antiviral activity, which offers an
opportunity for the development of a new anti-influenza virus agent. - 中文關鍵字: --
- 英文關鍵字: --