Drug combination therapy increases successful drug repositioning

Sun, Wei; Sanderson, Philip E.J.; Zheng, Wei

doi:10.1016/j.drudis.2016.05.015

Cited by 348 publications

(239 citation statements)

References 67 publications

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“…One of the main drawbacks for drug repurposing is that the new activity identified for an approved drug is usually not potent enough for the intended clinical application (Sun et al , 2016a). For example, the repurposed drug is not therapeutically effective at its approved dose due to the limited human plasma concentrations.…”

Section: Assays For Drug Repurposing Screensmentioning

confidence: 99%

“…Effective vaccines are still not available for many infectious diseases such as malaria, HIV, Ebola virus and Zika virus. The traditional process of development for a new low MW drug usually requires an average of 10 to 12 years and costs hundreds of millions of dollars (Sun et al , 2016a). Development of new broad spectrum antibiotics is increasingly difficult.…”

Section: Introductionmentioning

confidence: 99%

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Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

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221

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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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Section: Assays For Drug Repurposing Screensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Zheng

Sun

Simeonov

2017

British J Pharmacology

Self Cite

221

200

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“…Drug repurposing screens have recently emerged as an alternative approach to accelerate drug development 28,29 . Following a repurposing phenotypic screen, new indications for existing drugs may be rapidly identified and clinical trials can be carried out quickly, which is especially critical for rapidly spreading infectious diseases.…”

Section: Introductionmentioning

confidence: 99%

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

Lee

Wen

et al. 2016

Nat Med

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604

535

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In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ~6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds, and we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, Emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and 3-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, an FDA approved category B anthelmintic drug, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

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“…In pharmacokinetic studies, the maximum drug concentration in human blood or plasma is the peak drug concentration detected after the drug is administrated in an in vivo experiment. Weak potency and insufficient plasma concentration are the common issues encountered for the active compounds found from drug repurposing screens (Sun et al, 2016). In this study, we report a targeted drug combination approach and identification of unique three-drug combinations that synergistically block EBOV infection.…”

Section: Introductionmentioning

confidence: 99%

Synergistic drug combination effectively blocks Ebola virus infection

Sun

Martínez-Romero

et al. 2017

Antiviral Research

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Although a group of FDA-approved drugs were previously identified with activity against Ebola virus, most of them are not clinically useful because their human blood concentrations are not high enough to inhibit EBOV infection. We screened 795 unique three-drug combinations in an EBOV entry assay. Two sets of three-drug combinations, toremifene-mefloquine-posaconazole and toremifene-clarithromycin-posaconazole, were identified that effectively blocked EBOV entry and were further validated for inhibition of live EBOV infection. The individual drug concentrations in the combinations were reduced to clinically relevant levels. We identified mechanisms of action of these drugs: functional inhibitions of Niemann–Pick C1, acid sphingomyelinase, and lysosomal calcium release. Our findings identify the drug combinations with potential to treat EBOV infection.

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Drug combination therapy increases successful drug repositioning

Cited by 348 publications

References 67 publications

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen

Synergistic drug combination effectively blocks Ebola virus infection

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