To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 µg/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups.

To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. In these screenings, Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8µg/ml significantly, and the EC50 was determined with 2.5ng/ml. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus. Fluoxetine treatment resulted in a decrease in viral protein expression. Furthermore, Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. We see the role of Fluoxetine in the early treatment of SARS-CoV-2 infected patients of risk groups.Starting in December 2019, SARS-CoV-2 originated in central China became a pandemic thread with more than 7.000.000 cases worldwide and more than 400.000 deaths so far.Despite these high case rates Remdesivir, 1 the only effective treatment is still not available for most of the patients. At the same time, other promising substances like Lopinavir 2 and Chloroquine 3 showed little effect or led to severe adverse side effects. Furthermore, some drugs, such as ribavirin and interferon, 4 had no significant impact on patient survival rates.To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. 5 We decided to follow this path and screened approved medications "off-label" 6 against SARS-CoV-2. In such a trial, we investigated the effect of the serotonin reuptake receptor inhibitors (SRRI) Fluoxetine, Escitalopram, and Paroxetine on viral replication. For that, cytotoxicity and viral replication rates of a patient-derived virus isolate were measured. To investigate cytotoxicity, Vero cells were incubated with the compounds for three days, and cell growth was determined using a Perkin Elmer Ensight reader. The Vero cells were incubated with the compounds at increasing concentrations and subsequently infected with SARS-CoV-2 at an MOI of approx. 0.5. The concentrations were selected near the concentration used for the treatment of depression (e.g., 0.8 µg/ml for Fluoxetine). DMSO was used as solvent control. After three days, viral replication supernatants were collected and viral RNA was extracted using a MagNA Pure 24 system (Roche). Viral replication was quantified by real time RTqPCR with the LightMix Assay SARS-CoV-2 RdRP RTqPCR assay kit (TIB MOLBIOL, Germany) and the RNA Process Control kit (Roche) ( Figure 1A). The PCR was pipetted with a pipette robot device to ensure quality (BRAND, Germany). All infections were performed in triplicates and reaped twice. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8µg/ml significantly, and the EC50 was determin...

Although a potent Yellow fever vaccine is available since 1937, up to 200.000 severe cases are reported per year, which indicates that virus vaccines require additional support by antiviral therapies. Direct-acting antiviral drugs against severe and widespread diseases, such as DENV and Yellow fever infections with more than millions of diagnosed diseases per year, are still not available. Since antivirals' development against neglected diseases is uneconomical, a broadspectrum antiviral compound would be of public benefit. Here, we show that IMP-1088, a recently published myristoyltransferase-1/2 inhibitor suppressing Rhino- and Polioviruses, inhibits replication of HIV-1, Yellow fever virus, Dengue virus, Vaccinia virus, CMV, and human Herpesvirus 8 in the low nanomolar range, indicating that IMP-1088 has broad-range activity against different pathogenic virus families. The inhibition relies on virally encoded myristoylation signals since Zika, Chikungunya, and Enterovirus 71 are not affected by IMP-1088. Furthermore, we show that the Yellow fever NS5 protein is myristoylated and IMP-1088 treatment of Dengue and Yellow fever infected cells leads to a re-localisation of the viral NS5 proteins.