A screen of approved drugs and molecular probes identifies therapeutics with anti–Ebola virus activity

Johansen, Lisa M.; DeWald, Lisa Evans; Shoemaker, Charles J.; Hoffstrom, Benjamin G.; Lear-Rooney, Calli M.; Stossel, Andrea; Nelson, Elizabeth A.; Delos, Sue E.; Simmons, James A.; Grenier, Jill M.; Pierce, Linda M; Pajouhesh, Hassan; Lehár, Joseph; Hensley, Lisa E.; Glass, Pamela J.; White, Judith M.; Olinger, Gene G.

doi:10.1126/scitranslmed.aaa5597

Cited by 217 publications

(304 citation statements)

References 56 publications

(112 reference statements)

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“…This dataset overlaps to some extent with another review that identified over 60 molecules 15 . Two recent repurposing screens identified 53 16 and 80 17 compounds with antiviral activity which also overlap the earlier screens. Additional studies have identified small number of inhibitors 18, 19 .…”

Section: Introductionmentioning

confidence: 68%

“…Such an approach may be a useful way to leverage the HTS data that has already been developed at great cost. In this study we have focused on just the data from a single group 3, 31 but it may also be possible to combine this with the data from the other high throughput screens 2, 16, 17 to provide a much larger training set. There is also the opportunity to apply many different computational approaches beyond those described here to identify whole cell active compounds against EBOV.…”

Section: Discussionmentioning

confidence: 99%

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Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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“…Small-molecule drugs, like bepridil or sertraline, may cause side effects since they show cytotoxicity to cultured cells (18). Furthermore, to date, no drug candidate has been designed to block EBOV sexual transmission, which is a novel EBOV transmission pathway (10).…”

Section: Discussionmentioning

confidence: 99%

“…***, P Ͻ 0.001. which block viral entry by targeting two different sites on the Zaire GP (30,31). Then, we tested two small-molecule compounds, bepridil and sertraline, which have been considered inhibitors of EBOV function before or at the fusion step (18). As shown in Table 3, HP-HSA exhibited more potent Zaire PsV entry-inhibitory activity (lower EC 50 s and EC 90 s) than any of the drug candidates noted above.…”

Section: Fig 3 Ex Vivomentioning

confidence: 99%

“…This indicates that the antibody-based therapy cannot eliminate the EBOVs hidden in immune-privileged sites. Two small-moleculecompound drugs approved for use for the treatment of other diseases, bepridil and sertraline, were demonstrated to be EBOV entry inhibitors by targeting host proteins in the endosome (18). Nevertheless, at the dose efficient for anti-EBOV treatment in vitro, they still induce cytotoxicity, implying the possibility of side effects in vivo.…”

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confidence: 99%

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Chemically Modified Human Serum Albumin Potently Blocks Entry of Ebola Pseudoviruses and Viruslike Particles

Xia

et al. 2017

Antimicrob Agents Chemother

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Ebola virus (EBOV), the causative pathogen of the deadly Ebola virus disease (EVD), can be transmitted via contact with EVD patients, including sexual contact with EVD survivors. At present, no licensed vaccine or therapeutic is available. In this study, we compared eight anhydride-modified proteins for their entry-inhibitory activity against the pseudovirus (PsV) carrying the envelope glycoprotein (GP) of the EBOV Zaire or Sudan species (Zaire PsV and Sudan PsV, respectively). We found that 3-hydroxyphthalic anhydride-modified human serum albumin (HP-HSA) was the most effective in inhibiting the entry of both Zaire PsV and Sudan PsV, with the 50% effective concentration being at the nanomolar level and with HP-HSA being more potent than EBOV-neutralizing antibody MIL77-2 (4G7, a component antibody of the ZMapp drug cocktail). The combination of HP-HSA and MIL77-2 exhibited a synergistic effect. HP-HSA had no obvious in vitro or in vivo toxicity. The EBOV PsV entryinhibitory activity of HP-HSA remained intact after storage at 45°C for 8 weeks, suggesting that HP-HSA has the potential for worldwide use, including tropical regions in African countries, as either a therapeutic to treat EBOV infection or a prophylactic microbicide to prevent the sexual transmission of EBOV.

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Viruses

Berenji¹

2016

Physical and Biological Hazards of the Workplace

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A screen of approved drugs and molecular probes identifies therapeutics with anti–Ebola virus activity

Cited by 217 publications

References 56 publications

Machine learning models identify molecules active against the Ebola virus in vitro

Machine learning models identify molecules active against the Ebola virus in vitro

Chemically Modified Human Serum Albumin Potently Blocks Entry of Ebola Pseudoviruses and Viruslike Particles

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