Repurposing Antifungals for Host-Directed Antiviral Therapy?

Schloer, Sebastian; Goretzko, Jonas; Rescher, Ursula

doi:10.3390/ph15020212

Cited by 6 publications

(9 citation statements)

References 138 publications

(187 reference statements)

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“…Although both U18666A and bafilomycin A have antiviral activity in cell culture infection models, both agents are not approved for clinical use due to their unfavourable safety profiles [ 21–24 ]. To explore the suitability of our ex vivo mouse tissue model for drug assessment studies, we next included drugs that were already suggested to have repurposing potential for antiviral approaches [ 25 ]. The widely used antidepressant fluoxetine was already shown to inhibit IAV and SARS-CoV-2 infection in vitro [ 19 , 26 ], most likely based on its chemical nature as a functional inhibitor of the acid sphingomyelinase (FIASMA) in endolysosomes [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

Schloer

Treuherz

Faist

et al. 2022

Emerging Microbes & Infections

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Pandemic outbreaks of viruses such as influenza virus or SARS-CoV-2 are associated with high morbidity and mortality and thus pose a massive threat to global health and economics. Physiologically relevant models are needed to study the viral life cycle, describe the pathophysiological consequences of viral infection, and explore possible drug targets and treatment options. While simple cell culture-based models do not reflect the tissue environment and systemic responses, animal models are linked with huge direct and indirect costs and ethical questions. Ex vivo platforms based on tissue explants have been introduced as suitable platforms to bridge the gap between cell culture and animal models. We established a murine lung tissue explant platform for two respiratory viruses, influenza A virus (IAV) and SARS-CoV-2. We observed efficient viral replication, associated with the release of inflammatory cytokines and the induction of an antiviral interferon response, comparable to ex vivo infection in human lung explants. Endolysosomal entry could be confirmed as a potential host target for pharmacological intervention, and the potential repurposing potentials of fluoxetine and interferons for host-directed therapy previously seen in vitro could be recapitulated in the ex vivo model.

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Section: Resultsmentioning

confidence: 99%

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

Schloer

Treuherz

Faist

et al. 2022

Emerging Microbes & Infections

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“…Synthetic small antifungals could be classified into four major classes, including polyenes, flucytosine, echinocandins, and azoles, according to their differential functional targets and mechanisms [50]. Except for flucytosine which interferes with fungal nucleic acid synthesis, polyenes and azoles show antifungal effects resulting in compromised fungal membranes.…”

Section: Discussionmentioning

confidence: 99%

“…Except for flucytosine which interferes with fungal nucleic acid synthesis, polyenes and azoles show antifungal effects resulting in compromised fungal membranes. Polyenes bind to sterol components and form pores on the membrane, whereas azoles inhibit fungal sterol biosynthesis [50]. Unlike other antifungals, echinocandins exhibit effective antifungal activity by targeting 1,3-β-D glucan synthase.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases

Shěn

Zhang

Yin

et al. 2022

BMC Med

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Background The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5–30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment. Methods The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis. Results Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1. Conclusions The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases.

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“…Joint treatment with Mefloquine and Nelfinavir manifested synergistic antiviral activity in wide concentration ranges [124]. Itraconazole is a member of the triazole group of broad-spectrum antifungals [135]. The in vitro antiviral activities of itraconazole and its metabolite against SARS-CoV-2 were proved in low micromolar level [136].…”

Section: Other Antimicrobials For Combination Use Against Sars-cov-2mentioning

confidence: 99%

Combination Therapies against COVID-19

Luo¹,

Zheng²,

Zhang³

2022

Front. Biosci. (Landmark Ed)

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19), which was announced as a pandemic leading to devastating economic and medical burden worldwide. The virus attacks the organ system across the body by binding to its receptor (for example, angiotensin converting enzyme 2) on the surface of the host cell of various organs. The patients present with a variety of pathological symptoms ranging from fever, cough and cytokine storm to acute respiratory distress syndrome (ARDS). Many combination therapies have been developed to combat the disease, via blocking one or more processes of the viral life cycle and/or relieving host complications simultaneously. In this review, the progress of those combination therapies containing at least one small molecule is updated. We believe it'll provide significant inspiration for further development of treatment strategy against SARS-CoV-2, especially its mutant variants.

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Repurposing Antifungals for Host-Directed Antiviral Therapy?

Cited by 6 publications

References 138 publications

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

3D Ex vivo tissue platforms to investigate the early phases of influenza a virus- and SARS-CoV-2-induced respiratory diseases

Antiviral activity and mechanism of the antifungal drug, anidulafungin, suggesting its potential to promote treatment of viral diseases

Combination Therapies against COVID-19

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