Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

Finch, Courtney; Dyall, Julie; Xu, Shan; Nelson, Elizabeth A.; Postnikova, Elena; Liang, Janie; Zhou, Huanying; DeWald, Lisa Evans; Thomas, Craig J.; Wang, Amy; Xu, Xin; Hughes, Emma; Morris, Patrick J.; Mirsalis, Jon C.; Arolfo, María Pía; Koci, Bryan; Holbrook, Michael R.; Hensley, Lisa E.; Jahrling, Peter B.; Schmaljohn, Connie S.; Johansen, Lisa M.; Olinger, Gene G.; Schiffer, Joshua T.; White, Judith M.

doi:10.20944/preprints202102.0293.v1

Cited by 3 publications

(3 citation statements)

References 62 publications

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“…Sertraline is an antidepressant belonging to selective serotonin reuptake inhibitors. It has been reported to inhibit infection of the Ebola virus, Lassa virus, and arenavirus (Finch et al, 2021;Herring et al, 2021) via suppressing viral glycoprotein-mediated entry. Similarly, a more recent report indicated that sertraline prevented infection of Vero E6 cells with SARS-CoV-2 pseudoparticles and blocked SARS-CoV-2 S-protein-mediated cell fusion (Carpinteiro et al, 2020;Xiao et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

Peng

Ding

Jiang

et al. 2021

Sci. China Life Sci.

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo . In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF -α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro , suggesting promising application for COVID-19 treatment. Supporting Information The supporting information is available online at 10.1007/s11427-021-2031-7. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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Section: Discussionmentioning

confidence: 99%

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

Peng

Ding

Jiang

et al. 2021

Sci. China Life Sci.

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“…Prior to this study, the antiviral activity of sertraline has been reported only against a few viral groups including filoviruses and coronaviruses [36][37]. Sertraline acts as a functional inhibitor of acid sphingomyelinase (ASM) that impairs the enzymatic activity of low-pH-dependent, lysosomal ASM [38][39].…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Sertraline is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry Through Neutralization of Endolysosomal Acidification

Tseng¹,

Hsu²,

Ling³

et al. 2021

Preprint

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Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs to treat EV71 infections. In this study, we conducted an antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be relieved greatly by exposing virus-infected cells to extracellular low-pH culture media. Together, we have identified an FDA-approved antidepressant with the new indication for the broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

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“…Determining the synergistic effects of combining two mAbs for the treatment of EVD is challenging, and this combined approach has not been investigated in a clinical or laboratory trial (Crozier et al, 2022). Therefore, it is crucial to investigate the noninterference of the proposed products (ansuvimab and REGN-EB3) with important safety signals (Finch et al, 2021). There are significant differences between REGN-EB3 and ansuvimab in the production strategy and the mechanism of action.…”

Section: Potential Synergism Of Ansuvimab With Regn-eb3 (Inmazeb™)mentioning

confidence: 99%

Ebanga™: The most recent FDA-approved drug for treating Ebola

Taki

Ghanavati²,

Navidifar³

et al. 2023

Front. Pharmacol.

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Ebolavirus (EBOV) is a virulent pathogen that causes Ebola virus disease (EVD), which is a life-threatening human condition with a fatality rate of up to 90%. Since the first outbreak in Africa in 1976, several outbreaks and epidemics of EBOV have occurred across the globe. While EVD is recognized as a serious threat to human health and outbreaks occur almost every year, the treatment options for the disease are limited. In designing therapeutic strategies against EBOV infection, viral structural proteins, such as glycoprotein (GP), could be an excellent target for neutralizing the virus. According to the latest research, GP-specific antibodies are the most efficient post-exposure treatments for EVD. Ansuvimab-zykl, i.e., mAb114 (Ebanga™), is a recent FDA-approved human immunoglobulin monoclonal antibody targeting EBOV GP. This review provides a brief overview of the pharmacological effects and safety profile of ansuvimab in clinical trials and provides insights into the precise mechanism of this new drug for treating EVD.

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Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

Cited by 3 publications

References 62 publications

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

Antidepressant Sertraline is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry Through Neutralization of Endolysosomal Acidification

Ebanga™: The most recent FDA-approved drug for treating Ebola

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