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

Abstract

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.

Antiviral Screening of Multiple Compounds against Ebola Virus

“…Whereas omeprazole and esomeprazole demonstrated in vitro activity against EBOV, the results were in line with a previous report using pseudotyped viruses where the values of drug concentration causing 50% inhibition (IC 50 ) were in the region of 50 μM [10]. This suggested that doses required for potent inhibition would be difficult to achieve without concomitant and significant toxicity (the licenced dosing for 40 mg esomeprazole, 20 mg esomeprazole and 20 mg omeprazole generates median maximum plasma concentrations of 1.59–9.61 μM, 0.51–4.78 μM and 0.15–3.51 μM, respectively [36]).…”

“…Brief details of the compounds nominated for inclusion are outlined below:

Ouabain: Originally used for the treatment of heart diseases [5], which has been demonstrated to reduce EBOV replication by around half when testing in vitro in a study looking into the viral protein 24 (VP24) protein and the interruption of cellular interacting proteins [6]

17-DMAG: An inhibitor of heat shock protein 90 (HSP90), which has been shown to reduce in vitro EBOV replication [7]

BGB324: An inhibitor of Axl receptor tyrosine kinase, which appears to be involved with Ebola virus entry into host cells [8]

JB1a: An antibody therapy, targeting beta-1 integrins, which have been proposed to facilitate the entry of filoviruses; treatment of target cells with the JB1a clone reduced infection using a vesicular stomatitis virus (VSIV) pseudotyped with EBOV glycoprotein [9]

Omeprazole and esomeprazole magnesium: Members of the benzimidazoles that may stop viral entry via clathrin-mediated endocytosis by raising the endosomal pH. Both compounds were shown to inhibit lentivirus-based pseudotypes expressing EBOV glycoprotein [10]

Gleevec and Tasigna (market names for imatinib mesylate and nilotinib, respectively): Specific tyrosine kinase inhibitors originally developed as anticancer compounds and proposed to inhibit phosphorylation of the VP40 matrix protein which is required for EBOV exit from cells [11]. During large-scale screens of antivirals against EBOV, other groups have identified Gleevec [12] and Tasigna [13] as potential EBOV inhibitors…”

Values and Hopes of Ebola Vaccines Mass Immunization Programs and Treatments Adoption and Implementation Benefits in Africa

“…and 2x1010PU and 2x1011PU) respectively have demonstrated 100% efficacy in studies in nonhuman primates, but how that will translate to human subjects remains unknown as the minimum antibody titre needed to confer protection and common adverse events in humans is unknown. These studies will assess safety, side effects, and immunogenicity, including antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) and neutralization assays and T-cell immune responses as measured by intracellular cytokine [5,12,14]. Other potential therapies under identification, verification, safety and efficacy exploration include Favipiravir Brincidofovir, Interferons, ZMapp, Amodiaquine, Atorvostatin plus Irbesartan / Clomiphene and amiodarone [1].…”

“…Also effective and integrated coordination and community participation of both vulnerable and non as well as travellers in the context of Ebola epidemic response and vaccination is required. A number Ebola candidate vaccines are at preclinical and clinical stages in the development pipeline [10,11,13,14].There is a need for careful multicenter clinical trials documentation and long term pharmacovigilance to ensuring that mass immunization safety and efficacy outcomes. Also, reliable and sustainable surveillance and monitoring systems including vaccines procurement and supply chains management as well as other medical equipment are important at national and global level.…”

What's the host and what's the microbe? The Marjory Stephenson Prize Lecture 2015

“…More recently, we used HIV-based lentiviral vectors pseudotyped with 100 envelopes of different HIV-1 subtypes and strains to screen broadly neutralizing single chain antibodies from llamas (McCoy et al, 2012). Pseudotypes of gamma-retroviruses or lentiviruses bearing envelope glycoproteins of highly pathogenic enveloped viruses such as SARS coronavirus (Temperton et al, 2005), H5N1 influenza virus (Temperton et al, 2007), rabies and lyssaviruses (Wright et al, 2008) and Ebola filovirus (Long et al, 2015) have provided sensitive and specific neutralization serology of patients and vaccine recipients without the need for a high containment laboratory.…”