Identification of Diaryl-Quinoline Compounds as Entry Inhibitors of Ebola Virus

Viruses

Qinghua Cui¹  Ruikun Du¹  Rui Xiong²  Han Cheng³  Lijun Rong³  Manu Anantpadma⁴  RobertA. Davey⁴  Gang Zhang⁵ 

[1] College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and UICentre, University of Illinois at Chicago, Chicago, IL 60612, USA;Department of Microbiology and Immunology, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA;Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA;State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China;

关键词: EBOV;    entry inhibitor;    quinoline;    glycoprotein;    lead compound;    assay;   

DOI  :  10.3390/v10120678

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown