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Inhibition of SARS-CoV-2 infections of human lungs by functional inhibitors of the acid sphingomyelinase

Subject Area Virology
Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
Term from 2022 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 499449546
 
Final Report Year 2025

Final Report Abstract

The global health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to present significant challenges despite the widespread availability of vaccines and approved antiviral agents. The emergence of new viral variants with increased transmissibility and immune escape capabilities, along with the persistence of long-COVID symptoms in recovered patients, underscores the urgent need for alternative therapeutic strategies. This is especially critical in low- and middle-income countries, where access to current treatment options is often limited by availability, cost, and infrastructure. In recent years, functional inhibitors of acid sphingomyelinase (FIASMAs) have garnered attention as potential broad-spectrum antiviral agents. These drugs, which are primarily used as antidepressants, exert their antiviral effects by disrupting sphingolipid metabolism and interfering with viral entry and replication. Previous studies have indicated that FIASMAs such as fluoxetine, sertraline, and amitriptyline are capable of inhibiting infections caused by various viruses, including earlier strains of SARS-CoV-2. The present study aimed to evaluate and compare the antiviral efficacy of fluoxetine, sertraline, and amitriptyline against a panel of SARS-CoV-2 variants, including both early and recently emerged lineages. Using in vitro cell culture systems, the compounds were tested for their ability to inhibit infection by pseudotyped virus-like particles carrying spike proteins from different SARS-CoV-2 variants, as well as clinical virus isolates such as D614G, Alpha (B.1.1.7), Delta (B.1.617.2), Omicron BA.1, BA.5, and the recombinant subvariant XBB.1. All three FIASMAs demonstrated potent antiviral activity, significantly reducing viral entry and replication in a dose-dependent manner at subtoxic concentrations. Notably, their inhibitory effects were largely independent of spike protein mutations, suggesting a variant-agnostic mechanism of action. Among the tested compounds, amitriptyline showed particularly strong inhibition of viral replication, including against the highly immune-evasive Omicron sublineages. These findings align with and extend earlier reports on the antiviral potential of FIASMAs, further supporting their repositioning for the treatment of COVID-19. Given their well-characterized pharmacological profiles, widespread availability, and established safety in clinical use as antidepressants, fluoxetine, sertraline, and amitriptyline represent attractive candidates for rapid clinical deployment. Their ability to inhibit SARS-CoV-2 in vitro across multiple variants positions them as promising agents for both early intervention and potential adjunct therapy in COVID-19 patients, particularly in regions with limited healthcare access. In conclusion, this study highlights the antiviral potential of three clinically approved FIASMAs against a broad spectrum of SARS-CoV-2 variants. These results provide a compelling rationale for conducting large-scale, randomized clinical trials to assess their efficacy and safety in human populations. If successful, such repurposing efforts could expand the arsenal of affordable and accessible treatments for managing current and future waves of COVID-19.

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