Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry.

Jason Long,Edward Wright,Nigel Temperton,Eleonora Molesti,Wendy Barclay

doi:10.12688/f1000research.6085.2

Jason Long, Edward Wright + Show 3 more

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Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV.

Highlights

Emerging pathogens such as Ebolaviruses (EBOV), Avian Influenza viruses, Severe Acute Respiratory Syndrome (SARS) virus, Middle-East coronavirus (MERS), Chikungunya virus (CHIKV) and Dengue virus pose public health challenges that demand researchers and governments work together to assess their pandemic potential and plan mitigating strategies
pseudotype viruses (PVs) were generated bearing the envelope glycoproteins from Zaire ebolavirus (Mayinga strain) (EBOV-Z), Bundibugyo ebolavirus (EBOV-B), Marburg (Lake Victoria isolate) virus (MARV), H5 HA from a highly pathogenic avian influenza virus A/turkey/ England/50-92/91(H5N1) (FLU-H5), and Gibbon Ape Leukaemia virus (GALV)
In order to assess the ability of CQ, bafilyomycin A1 (BafA1), OM and ESOM to inhibit PV entry, drugs were serially diluted in triplicate in white bottomed 96-well plates

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Introduction

Emerging pathogens such as Ebolaviruses (EBOV), Avian Influenza viruses, Severe Acute Respiratory Syndrome (SARS) virus, Middle-East coronavirus (MERS), Chikungunya virus (CHIKV) and Dengue virus pose public health challenges that demand researchers and governments work together to assess their pandemic potential and plan mitigating strategies. Towards the end of 2014 the trend in case numbers reversed in Liberia and the epidemic slowed in Sierra Leone and Guinea, but the virus continues to transit in new geographical areas[5]. This epidemic has triggered a significant global health response relying on primary hygiene and other containment measures that have proved successful in limiting the spread of the virus in previous outbreaks. Several clinically approved drugs have been identified by researchers[17,18,19,20], including amiodarone, one of the several cationic amphiphiles found to inhibit filovirus entry which is currently being trialled in Sierra Leone[21]. The anti-malarial drug chloroquine (CQ) has been shown to inhibit EBOV entry and protected mice from EBOV infection[18,22] and has been previously highlighted as a possible drug to treat EBOV infection[11]

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