Synergistic drug combination effectively blocks Ebola virus infection

Sun, Wei; He, Shihua; Martínez-Romero, Carles; Kouznetsova, Jennifer; Tawa, Gregory J.; Xu, Miao; Shinn, Paul; Fisher, Ethan G; Long, Yan; Motabar, Omid; Yang, Shu; Sanderson, Philip E.J.; Williamson, Peter R.; Garcı́a-Sastre, Adolfo; Qiu, Xiangguo; Zheng, Wei

doi:10.1016/j.antiviral.2016.11.017

Cited by 85 publications

(74 citation statements)

References 30 publications

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“…Though antihistamines and antihistamine-like compounds cp15 and cp19 are likely to act through preventing Ebola GP mediated fusion via directly binding to the GP protein, other possible mechanisms of action may exist. Recently, many cationic amphiphilic drugs (CADs) have been reported to be able to inhibit Ebola virus infection at a late entry stage (Fan et al, 2017; Johansen et al, 2015; Shoemaker et al, 2013; Sun et al, 2017). CADs are a wide group of chemicals with structure features of a hydrophobic aromatic ring system and a hydrophilic side-chain containing an ionizable amine.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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Filoviruses, consisting of Ebola virus, Marburg virus and Cuevavirus, cause severe hemorrhagic fevers in humans with high mortality rates up to 90%. Currently, there is no approved vaccine or therapy available for the prevention and treatment of filovirus infection in humans. The recent 2013–2015 West African Ebola epidemic underscores the urgency to develop antiviral therapeutics against these infectious diseases. Our previous study showed that GPCR antagonists, particularly histamine receptor antagonists (antihistamines) inhibit Ebola and Marburg virus entry. In this study, we screened a library of 1220 small molecules with predicted antihistamine activity, identified multiple compounds with potent inhibitory activity against entry of both Ebola and Marburg viruses in human cancer cell lines, and confirmed their anti-Ebola activity in human primary cells. These small molecules target a late-stage of Ebola virus entry. Further structure-activity relationship studies around one compound (cp19) reveal the importance of the coumarin fused ring structure, especially the hydrophobic substituents at positions 3 and/or 4, for its antiviral activity, and this identified scaffold represents a favorable starting point for the rapid development of anti-filovirus therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…We then carried out a new screening of synergistic drug combinations with individual drug concentrations relevant to human plasma concentrations. Several three‐drug combinations with the clinically relevant drug concentrations that effectively suppressed Ebola virus infection in vitro were identified (Sun et al , 2017) (Table 2B and Figure 4). …”

Section: Synergistic Drug Combinations For Infectious Diseasesmentioning

confidence: 99%

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

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Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug‐resistant pathogens is a big challenge for treatment of infectious diseases. In addition, outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug‐resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared with previous decades. In parallel with this, is an increase in the number of drug‐resistant bacteria. For these threats and challenges to be countered, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combinations using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutic agents such as narrow spectrum antibiotics against drug‐resistant bacteria for these global challenges.Linked ArticlesThis article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc

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“…Zheng et al screened 795 unique three-drug combinations in an EBOV entry assay. 52 This result was further validated in a mice model for EBOV infection in which the rate of survival for both combinations was 74% and >90%, respectively.…”

Section: Combination Of Molecules With Different Entry Targetsmentioning

confidence: 69%

Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

Fanunza

Frau

Corona

et al. 2018

Annual Reports in Medicinal Chemistry

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Synergistic drug combination effectively blocks Ebola virus infection

Cited by 85 publications

References 30 publications

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

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

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Antiviral Agents Against Ebola Virus Infection: Repositioning Old Drugs and Finding Novel Small Molecules

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