The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry

Gehring, Gerrit; Rohrmann, Katrin; Atenchong, Nkacheh; Mittler, Eva; Becker, Stephan; Dahlmann, Franziska; Pöhlmann, Stefan; Vondran, Florian W. R.; David, Sascha; Manns, Michael P.; Ciesek, Sandra; Hahn, Thomas von

doi:10.1093/jac/dku091

Cited by 167 publications

(178 citation statements)

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“…No preclinical reports have assessed amiodarone in an animal model of filovirus infection. Amiodarone has been reported to inhibit filovirus cell entry in vitro 186 and interfere with fusion of the EBOV viral envelope with the endosomal membrane 187 .…”

Section: Buffy Coatmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Buffy Coatmentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

111

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“…Another recent study has shown three approved ion channel blockers (amiodarone, dronedarone, and verapamil) inhibited EBOV cellular entry 9 . The drugs were given at concentrations that would be achieved in human serum, and were effective against several of the filoviruses 9 . None of the FDA approved drugs described in these various studies were designed to target the Ebola virus.…”

Section: Introductionmentioning

confidence: 98%

“…We have previously summarized the numerous small molecules described in the literature as possessing antiviral activity that could be further evaluated for their potential EBOV activity alongside the few new antivirals. We have found that there is considerable prior knowledge regarding these small molecules possessing activity against EBOV in vitro or in animal models 5– 8 , and this includes a number of accessible FDA-approved drugs 2, 3, 9 . Another recent study has shown three approved ion channel blockers (amiodarone, dronedarone, and verapamil) inhibited EBOV cellular entry 9 .…”

Section: Introductionmentioning

confidence: 99%

“…We have found that there is considerable prior knowledge regarding these small molecules possessing activity against EBOV in vitro or in animal models 5– 8 , and this includes a number of accessible FDA-approved drugs 2, 3, 9 . Another recent study has shown three approved ion channel blockers (amiodarone, dronedarone, and verapamil) inhibited EBOV cellular entry 9 . The drugs were given at concentrations that would be achieved in human serum, and were effective against several of the filoviruses 9 .…”

Section: Introductionmentioning

confidence: 99%

“…Some have suggested that G-protein-coupled receptors (GPCRs) may play a role in filoviral entry and receptor antagonists could be developed as anti-EBOV therapies 12 . The compounds which are FDA-approved drugs for other diseases 2, 3, 9 but with activity against EBOV in vitro or in vivo may represent useful starting points with the advantage that much is known regarding their absorption, distribution, metabolism and excretion (ADME) and toxicity properties. Thus, these repurposed drugs may represent a more advanced starting point for therapeutic development and approval compared with new chemical entities for preventing the spread and mortality associated with EBOV.…”

Section: Introductionmentioning

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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Retroviral Pseudotypes – From Scientific Tools to Clinical Utility

Temperton

Wright

Scott

2015

Encyclopedia of Life Sciences

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Retroviral pseudotypes are important research and diagnostic tools for basic and clinical virology studies, facilitating the detailed investigation of individual genes, cellular receptors, antibody responses, serosurveillance and antiviral therapies. Importantly, pseudotypes enable the study of highly pathogenic viruses, without the need for high containment. Their use as gene therapy vectors is widely documented, but other uses, once less well known, are becoming more prominent. The substitution of envelope proteins expressed on the virion surface enables pseudotypes to be employed as surrogates for wildtype viruses in antibody neutralisation or antiviral screening assays and for the study of cell–virus receptor interactions. In addition, they are increasingly being utilised as vaccine immunogens, expressing the antigen either on the particle surface or as a transfer gene for cellular expression. These studies demonstrate the potential for using pseudotypes for both scientific and clinical applications. Key Concepts Students will learn: What are retroviral pseudotypes. How they are constructed and titrated. The common elements that comprise a retroviral pseudotype. How retroviral pseudotypes can be used to deliver genes. How they can be used as tools for the study of viral attachment, entry and receptor identification. About using pseudotypes as surrogate viruses in antibody neutralisation assays. The use of pseudotypes to measure vaccine immunogenicity and screen for antiviral activity and resistance. How pseudotypes can be used as experimental vaccines.

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The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry

Abstract: The ion channel blockers amiodarone, dronedarone and verapamil inhibit filoviral cell entry.

Cited by 167 publications

References 55 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

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

Retroviral Pseudotypes – From Scientific Tools to Clinical Utility

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