Ebola virus (EBOV) infection: Therapeutic strategies

Clercq, Erik De

doi:10.1016/j.bcp.2014.11.008

Cited by 72 publications

(61 citation statements)

References 83 publications

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“…However, in the event of another outbreak, that experimental niche should probably be filled by one of a small number of other promising, but unproven, treatments that have emerged since the beginning of the recent crisis. 25–27 As new epidemics emerge, undoubtedly coupled with their own set of challenges, it is important that any experimental interventions be evaluated in as rigorous a manner as possible so that their success or failure can be declared with the confidence that public health policy demands.…”

Section: Discussionmentioning

confidence: 99%

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

2016

N Engl J Med

434

200

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BACKGROUND Data from studies in nonhuman primates suggest that the triple monoclonal antibody cocktail ZMapp is a promising immune-based treatment for Ebola virus disease (EVD). METHODS Beginning in March 2015, we conducted a randomized, controlled trial of ZMapp plus the current standard of care as compared with the current standard of care alone in patients with EVD that was diagnosed in West Africa by polymerase-chain-reaction (PCR) assay. Eligible patients of any age were randomly assigned in a 1:1 ratio to receive either the current standard of care or the current standard of care plus three intravenous infusions of ZMapp (50 mg per kilogram of body weight, administered every third day). Patients were stratified according to baseline PCR cycle-threshold value for the virus (≤22 vs. >22) and country of enrollment. Oral favipiravir was part of the current standard of care in Guinea. The primary end point was mortality at 28 days. RESULTS A total of 72 patients were enrolled at sites in Liberia, Sierra Leone, Guinea, and the United States. Of the 71 patients who could be evaluated, 21 died, representing an overall case fatality rate of 30%. Death occurred in 13 of 35 patients (37%) who received the current standard of care alone and in 8 of 36 patients (22%) who received the current standard of care plus ZMapp. The observed posterior probability that ZMapp plus the current standard of care was superior to the current standard of care alone was 91.2%, falling short of the prespecified threshold of 97.5%. Frequentist analyses yielded similar results (absolute difference in mortality with ZMapp, −15 percentage points; 95% confidence interval, −36 to 7). Baseline viral load was strongly predictive of both mortality and duration of hospitalization in all age groups. CONCLUSIONS In this randomized, controlled trial of a putative therapeutic agent for EVD, although the estimated effect of ZMapp appeared to be beneficial, the result did not meet the prespecified statistical threshold for efficacy. (Funded by the National Institute of Allergy and Infectious Diseases and others; PREVAIL II ClinicalTrials.gov number, NCT02363322.)

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Section: Discussionmentioning

confidence: 99%

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

2016

N Engl J Med

434

200

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“…Although unexplained hemorrhage (such as bruising and bleeding), kidney and liver dysfunction, cardiovascular distress and hypovolemic shock may occur as well in more serious cases [3][4][5][6]. Although several compounds have been proposed to treat this pathogenic disease [7][8][9][10][11][12][13][14][15], neither approved antiviral drugs nor vaccines are available in the market right now, and most of the drugs that have been given for the Ebola patients only meant to reduce the current symptoms, not directly targeting the virus [16]. Moreover, the extortionate cost of the newly-developed, non-FDA-approved drug makes the Ebola treatment, especially in poverty areas such as Africa, render ineffective [17].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel Ebola virus (EBOV) VP24 inhibitor from Indonesian natural products through in silico drug design approach

Tambunan¹,

Nasution²

2017

AIP Conference Proceedings

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Sensitivity differences between microporous NaY and hierarchical ZSM-5 modified electrodes as ammonia gas sensor AIP Conference Proceedings 1862, 030081 (2017) Abstract. Ebola remains as one of the deadliest diseases in the world, with almost 29,000 cases were reported and kill 11,000 of them, and yet neither treatment nor vaccine that can combat this disease effectively. This disease is caused by ebolavirus (EBOV), a primary member of Filoviridae family. The life cycle of this virus has been operated by several key proteins, one of them is VP24 protein, which has been known for its crucial role in the transcription and replication of EBOV. Therefore, targeting VP24 protein can be a solution for treating this pathogenic disease. In this study, virtual screening of Indonesian natural products as EBOV VP24 inhibitor was performed. About 2,020 ligands from many sources, including HerbalDB database, were obtained and screened by using DataWarrior software to measure its molecular and pharmacological properties, resulting 301 ligands in the process. Then, the molecular docking simulation was performed to check the ligand's binding interaction and affinity with EBOV VP24 protein; this simulation was done by using MOE 2014.09 software. This study resulted that cycloartocarpin was the best ligand to inhibit the EBOV VP24 protein. Therefore, this ligand should be checked its stability through molecular dynamics simulation and performed in vitro test to verify its bioactivity against the EBOV VP24 protein.

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“…Beyond these early stage drugs, there are a number of other compounds that have also been identified as active against EBOV (summarized in a review 13 ). A thorough literature search identified 55 molecules suggested to have activity against EBOV in vitro and/or in vivo which were evaluated from the perspective of an experienced medicinal chemist as well as using simple molecular properties and ultimately 16 were highlighted as desirable 14 .…”

Section: Introductionmentioning

confidence: 99%

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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Ebola virus (EBOV) infection: Therapeutic strategies

Cited by 72 publications

References 83 publications

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection

Identification of novel Ebola virus (EBOV) VP24 inhibitor from Indonesian natural products through in silico drug design approach

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

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