Targeting viral entry as a strategy for broad-spectrum antivirals

Mazzon, Michela; Marsh, Mark

doi:10.12688/f1000research.19694.1

Cited by 82 publications

(83 citation statements)

References 92 publications

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“…Our results support the hypothesis that although there is quite some variation in the actual escape mechanisms (11), targeting the viral entry might serve as a target for antiviral therapy (30). The intricate regulatory circuits that underly endolysosomal lipid balance and functionality are key elements functioning at the endolysosomal host-virus interface and are promising druggable targets for a wide variety of viruses and might be a fast and versatile approach to fight a broad range of pathogens with functionally similar modes of action.…”

Section: Discussionsupporting

confidence: 79%

Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

Schloer

Brunotte

Goretzko

et al. 2020

Preprint

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The Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibits the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract SARS-CoV-2 and COVID 19.SignificanceOnly very limited therapeutic options are clinically available for treatment of Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2), and the development of safe, effective, and globally available pharmaceuticals are urgently required. We report that the widely used antidepressant fluoxetine efficiently inhibits the early entry and propagation of SARS-CoV-2 in the cell culture model, and may offer a promising approach for host-directed therapy to counteract SARS-CoV-2 and COVID 19.

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Section: Discussionsupporting

confidence: 79%

Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

Schloer

Brunotte

Goretzko

et al. 2020

Preprint

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“…The viruses utilize pH sensing as an evolutionary strategy to monitor the endosomal maturity. Two major sensing strategies utilized by the viruses for induction of membrane fusion are direct sensing of the pH leading to conformational changes in the membrane glycoproteins and enzyme-mediated proteolytic cleavage [18]. Increase in this pH can hence lead to inhibition of viral fusion and replication.…”

Section: Action On Vacuolar Atpase and Impact On Phmentioning

confidence: 99%

The Potential Therapeutic Role of Proton Pump Inhibitors in COVID-19: Hypotheses Based on Existing Evidences

2020

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Although the major therapeutic uses of the proton pump inhibitors are in gastric-acid related diseases, evidences are suggestive of a pleiotropic nature of the compounds. We comment on the probable pathways and cellular machineries via which proton pump inhibitors could show beneficial therapeutic effects against SARS-CoV-2 based on the existing evidences. Proton pump inhibitors have shown antiviral potencies in various in vivo and in vitro studies. Some of the major possible ways through which they can act against SARS-CoV-2 are by exerting anti-inflammatory and anti-fibrotic effects, via vacuolar ATPase pumps leading to raised endolysosomal pH and by targeting endosomal complexes. The current pandemic has put forward a challenge to find treatment options. Although the potential roles of proton pump inhibitors against SARS-CoV-2 have been discussed in recent publications, the clinical evidences for their real-world effectiveness do not point towards a beneficial effect clearly yet. We suggest that although proton pump inhibitors should strongly be considered as potential therapeutic options for COVID-19, larger studies in the form of randomized controlled trials would be required to arrive at a definite conclusion.

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“…Viral cellular entry is the first step for the establishment of a productive viral infection 5 . Effective inhibition of viral entry is an important goal for the development of antiviral antibodies, vaccines, and drugs [6][7][8] . The cell entry of SARS-CoV-2 is mediated by viral spike (S) glycoprotein and its interaction with the cellular ACE2 receptor [9][10][11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compound inhibitors

Zhang

Wang

et al. 2020

Preprint

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The ongoing COVID-19 pandemic, caused by SARS-CoV-2 infection, has resulted in hundreds of thousands of deaths. Cellular entry of SARS-CoV-2, which is mediated by the viral spike protein and host ACE2 receptor, is an essential target for the development of vaccines, therapeutic antibodies, and drugs. Using a mammalian cell expression system, we generated a recombinant fluorescent protein (Gamillus)-fused SARS-CoV-2 spike trimer (STG) to probe the viral entry process. In ACE2-expressing cells, we found that the STG probe has excellent performance in the live-cell visualization of receptor binding, cellular uptake, and intracellular trafficking of SARS-CoV-2 under virus-free conditions. The new system allows quantitative analyses of the inhibition potentials and detailed influence of COVID-19-convalescent human plasmas, neutralizing antibodies and compounds, providing a versatile tool for high-throughput screening and phenotypic characterization of SARS-CoV-2 entry inhibitors. This approach may also be adapted to develop a viral entry visualization system for other viruses.

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Targeting viral entry as a strategy for broad-spectrum antivirals

Cited by 82 publications

References 92 publications

Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

The Potential Therapeutic Role of Proton Pump Inhibitors in COVID-19: Hypotheses Based on Existing Evidences

Virus-free and live-cell visualizing SARS-CoV-2 cell entry for studies of neutralizing antibodies and compound inhibitors

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