Identification of a coumarin-based antihistamine-like small molecule as an anti-filoviral entry inhibitor

Cheng, Han; Schafer, Adam; Soloveva, Veronica; Gharaibeh, Dima N.; Kenny, Tara; Retterer, Cary; Zamani, Rouzbeh; Bavari, Sina; Peet, Norton P.; Rong, Lijun

doi:10.1016/j.antiviral.2017.06.015

Cited by 30 publications

(23 citation statements)

References 38 publications

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“…Some of these inhibitors are shown in Figure . Other studies include the identification of coumarin‐based antihistamine‐like molecules, benzoquinoline compounds (SW456 compound reported to be the most potent compound in the infectious EBOV assay, IC 50 = 0.5 μM), ellagic acid (IC 50 = 1.4 μM), and vindesine (IC 50 = 0.34 μM), that proved to have potential EBOV inhibition.…”

Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration‐approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category‐A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small‐molecule antiviral drugs, small‐interference RNA molecules, phosphorodiamidate morpholino oligomers, full‐length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery.

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Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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“…Numerous small molecule therapeutic candidates that directly target the EBOV GP or critical host factors for viral entry have been reported. Most of these inhibitors target events occurring in the endosome, such as GP proteolytic processing, endosomal trafficking, interactions with NPC1, and fusion, including: (1) CA-074, FY-DMK, CID23631927, K11777, and cathepsin B and L inhibitors [29,30,37,38,39,40,41]; (2) inhibitors targeting host factors in the late endosomal steps in EBOV entry, such as U18666A, MBX2254, and MBX2270, targeting NPC1 [19,20,42], and numerous L-type calcium channel inhibitors, including verapamil, tetrandrine, nimodipinee, and diltiazem [10]; (3), a group of selective estrogen receptor modulators (SERMs), such as clomiphene and toremifene, which can directly bind to Ebola GP [36,43]; and (4) numerous G-protein coupled receptor (GPCR) antagonists such as antihistamines, targeting Ebola virus (and Marburg virus) GPs [34,44]. Only the first generation of antihistamines, such as diphenhydramine and chlorcyclizine, effectively block entry of Ebola virus and Marburg viruses, consistent with the notion that these compounds exert their antiviral effect in the endosomes [26].…”

Section: Discussionmentioning

confidence: 99%

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

Cui

Cheng

Xiong

et al. 2018

Viruses

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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.

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“…Recently, a screening of a library of 1220 small molecules with predicted anti-histamine activity identified many compounds with potent inhibitory activity against EBOV infection. Data about the structure-activity relation are extremely useful to find a good scaffold representing a favorable starting point for the rapid development of anti-EBOV therapeutic compounds [88].…”

Section: Psychoactive Drugsmentioning

confidence: 99%

Ebolavirus Entry: From Molecular Characterization to Drug Discovery

Salata¹,

Calistri²,

Alvisi³

et al. 2019

Preprint

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Ebola Virus Disease (EVD) is one of the most lethal transmissible infections characterized by a high fatality rate, and caused by members of the Filoviridae family. The recent large outbreak of EVD in West Africa (2013-2016), highlighted the worldwide danger of this disease and its impact on global public health and economy. The development of highly needed anti-Filoviridae antivirals has been so far hampered by the shortage of tools to study their life cycle in vitro, and therefore screen for potential active compounds outside a biosafety level-4 (BSL-4) containment. Importantly, the development of surrogate models to in vitro study of Filoviridae entry in a BSL-2 setting, such as viral pseudotypes and Ebola virus like particles, tremendously boosted both our knowledge on viral life cycle and the identification of promising anti-Filoviridae compounds interfering with viral entry. In this context, the combination of such surrogate systems with large-scale small molecule compounds and haploid genetic screenings, as well as rational drug design and drug repurposing approaches will prove priceless in our quest for the development of a treatment for EVD.

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Identification of a coumarin-based antihistamine-like small molecule as an anti-filoviral entry inhibitor

Cited by 30 publications

References 38 publications

Perspectives towards antiviral drug discovery against Ebola virus

Perspectives towards antiviral drug discovery against Ebola virus

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

Ebolavirus Entry: From Molecular Characterization to Drug Discovery

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