Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus

Mukhopadhyay, Rupkatha; Roy, Suheeta; Venkatadri, Rajkumar; Su, Yu‐Ping; Ye, Wenjuan; Barnaeva, Elena; Griner, Lesley Mathews; Southall, Noel; Hu, Xin; Wang, Amy Q.; Xu, Xin; Dulcey, Andrés E.; Marugán, Juan; Ferrer, Marc; Arav‐Boger, Ravit

doi:10.1371/journal.ppat.1005717

Cited by 59 publications

(62 citation statements)

References 63 publications

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“…It is also used to induce vomiting. In addition, it possessed antiviral effects against ZIKV, EBOV, RABV, CMV, HCoV-OC43, HSV-2, EV1, HMPV, RVF, FLUAV, HIV-1 and SARS-CoV-2 (Andersen et al, 2019;Chaves Valadao et al, 2015;Choy et al, 2020;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Shen et al, 2019;Yang et al, 2018) (https://doi.org/10.1101/2020.03.25.008482). Emetine was proposed to inhibit viral polymerases, though it could have some other targets (Khandelwal et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

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As of May 2020, the number of people infected with SARS-CoV-2 continues to skyrocket, with more than 4,5 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. Developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent plasma and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here we developed a neutralization assay using SARS-CoV-2 virus and monkey Vero-E6 cells. We identified most potent sera from recovered patients for treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against SARS-CoV-2 infection in Vero-E6 cells and identified antiviral activity of nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that combinations of virus-directed drug nelfinavir with host-directed drugs, such as salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine exhibit synergistic effect against SARS-CoV-2 in vitro. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Potential antiviral options against SARS-CoV-2 infection

Ianevski

Yao

Fenstad

et al. 2020

Preprint

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“…Given that emetine also inhibits ZIKV, EBOV, RABV, CMV, HCoV-OC43 and HIV-1 infections (Chaves Valadao et al, 2015;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Shen et al, 2019;Yang et al, 2018), and that it is an FDA-approved antiprotozoal drug, it may represent a promising safe-in-man BSAA candidate. (Carter and Shieh, 2015).…”

Section: Discovery Of Novel Bsaa Activities In Immortalized Cell Cultmentioning

confidence: 99%

Discovery and development of safe-in-man broad-spectrum antiviral agents

Andersen

Ianevski

Lysvand

et al. 2020

International Journal of Infectious Diseases

198

108

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# Contributed equally J o u r n a l P r e -p r o o f Highlights  We reviewed discovery and development process of broad-spectrum antiviral agents.  We summarized the information on 119 safe-in-man agents in freely accessible database.  Further studies will increase the number of broad-spectrum antivirals, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections. Abstract: Viral diseases are one of the leading causes of morbidity and mortality in the world. Virus-specific vaccines and antiviral drugs are the most powerful tools to combat viral diseases. However, broad-spectrum antiviral agents (BSAAs, i.e. compounds targeting viruses belonging to two or more viral families) could provide additional protection of general population from emerging and reemerging viral diseases reinforcing the arsenal of available antiviral options. Here, we reviewed discovery and development of BSAAs and summarized the information on 119 safe-in-man agents in freely accessible database (https://drugvirus.info/). Future and ongoing pre-clinical and clinical studies will increase the number of BSAAs, expand spectrum of their indications, and identify drug combinations for treatment of emerging and re-emerging viral infections as well as co-infections. J o u r n a l P r e -p r o o f 2015). Antiviral drugs and vaccines are used to fight viral infections in human (De Clercq and Li, 2016; Marston et al., 2014). Previously, there has been a focus on "one drug, one virus" dogma, which relied on targeting virus-specific factors. A counterpoint to this is "one drug, multiple viruses" paradigm, which came with the discovery of broad-spectrum antiviral agents (BSAAs), small-molecules that inhibit a wide range of human viruses (Bekerman and Einav, 2015; de Clercq and Montgomery, 1983; Debing et al., 2015; Ianevski et al., 2019; Rada and Dragun, 1977; Sidwell et al., 1972). This paradigm was based on the observation that different viruses utilize similar pathways and host factors to replicate inside a cell (Bosl et al., 2019). Although the concept of BSAAs has been around for almost 50 years, the field received a new impetus with recent outbreaks of Ebola, Zika, Dengue, influenza and other viral infections, the discovery of novel host-directed agents as well as development of drug repositioning methodology. Drug repurposing, also called repositioning, redirecting, reprofiling, is a strategy for generating additional value from an existing drug by targeting disease other than that for which it was originally intended (Nishimura and Hara, 2018; Pushpakom et al., 2019). This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in pre-clinical (animal model) and early clinical developmental phases (phase 0, I and IIa) are already available (Figure 1). Therefore, repositioning of launched or even failed drugs to viral diseases provides unique translational opportunities, includi...

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“…However, its potential cardiotoxicity has restricted its clinical use in the recent years. It was found to process antiviral activity against a broad range of RNA and DNA viruses, including Zika virus, Ebolavirus, Cytomegalovirus, rabies virus, HIV-1, echovirus 1, buffalo poxvirus, bovine herpesvirus 1, peste des petits ruminants virus, Newcastle disease virus, herpes simplex virus-2, metapneumovirus, Rift Valley fever virus, and influenza (Andersen et al, 2019;Chaves Valadao et al, 2015;Khandelwal et al, 2017;MacGibeny et al, 2018;Mukhopadhyay et al, 2016;Yang et al, 2018). Emetine was also identified to inhibit hCoV-OC43, hCoV-NL43, SARS-CoV, MERS-CoV, and MHV-A59 in vitro with EC 50 reported at low micromolar range (Dyall et al, 2014;Shen et al, 2019).…”

mentioning

confidence: 99%

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

et al. 2020

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An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 μM, 26.63 μM, 2.55 μM and 0.46 μM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 μM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 μM in combination with emetine at 0.195 μM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.

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Efficacy and Mechanism of Action of Low Dose Emetine against Human Cytomegalovirus

Cited by 59 publications

References 63 publications

Potential antiviral options against SARS-CoV-2 infection

Potential antiviral options against SARS-CoV-2 infection

Discovery and development of safe-in-man broad-spectrum antiviral agents

Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro

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