Abstract
Ebola virus is the causative agent of Ebola virus disease in humans. The lethality of Ebola virus infection is about 50%, supporting the urgent need to develop anti-Ebola drugs. Glycoprotein (GP) is the only surface protein of the Ebola virus, which is functionally critical for the virus to attach and enter the host cells, and is a promising target for anti-Ebola virus drug development. In this study, using the recombinant HIV-1/Ebola pseudovirus platform we previously established, we evaluated a small molecule library containing various quinoline compounds for anti-Ebola virus entry inhibitors. Some of the quinoline compounds specifically inhibited the entry of the Ebola virus. Among them, compound SYL1712 was the most potent Ebola virus entry inhibitor with an IC50 of ~1 μM. The binding of SYL1712 to the vial glycoprotein was computationally modeled and was predicted to interact with specific residues of GP. We used the time of the addition assay to show that compound SYL1712 blocks Ebola GP-mediated entry. Finally, consistent with being an Ebola virus entry inhibitor, compound SYL1712 inhibited infectious Ebola virus replication in tissue culture under biosafety level 4 containment, with an IC50 of 2 μM. In conclusion, we identified several related molecules with a diaryl-quinoline scaffold as potential anti-EBOV entry inhibitors, which can be further optimized for anti-Ebola drug development.
Highlights
The species Zaire Ebola virus, a member of the genus Ebola virus in the family Filoviridae is considered a significant public health concern due its high fatality rate
We screened a small library of bedaquiline derivatives for potential novel Ebola virus entry inhibitors using a pseudotyped (HIV-1/EBOV) entry assay [32]
We used an HIV-1-based pseudotyped virus screening platform to evaluate a small library of diarylquinoline compounds, and we identified a number of Ebola virus-specific entry inhibitors
Summary
The species Zaire Ebola virus, a member of the genus Ebola virus in the family Filoviridae is considered a significant public health concern due its high fatality rate. The infection can cause Ebola virus disease (EVD), which is a lethal acute hemorrhagic disease [1]. In the past 40 years, more than 30 Ebola virus disease outbreaks in African countries have been recorded. In 2013–2016, a large-scale epidemic broke out in Western Africa, and more than 10,000 deaths were confirmed. The. Viruses 2018, 10, 678; doi:10.3390/v10120678 www.mdpi.com/journal/viruses. Viruses 2018, 10, 678 most recent EVD epidemic was reported in the Democratic Republic of the Congo in 2018, which was first reported in May [2]. The development ofPEER anti-EBOV agents has been hampered partly due to the biosafety level 4
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