27Drug repositioning is the only feasible option to address the COVID-19 global challenge 28 immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were 29 pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates 30 against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and 31 in particular, two FDA-approved drugs -niclosamide and ciclesonidewere notable in some 32 respects. 33 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from 34 COVID-19 is an emerging infectious disease caused by a novel coronavirus, SARS-CoV-2 (1). 35Although the case fatality rate due to this viral infection varies from 1 to 12% (2), the 36 transmission rate is relatively high (3) and recently, the WHO declared COVID-19 outbreak a 37 pandemic. Currently, there is no vaccines or therapeutics available and the patients with COVID-38 19 are being treated with supportive care. 39Drug repositioning could be an effective strategy to respond immediately to emerging infectious 40 diseases since the new drug development usually takes more than 10 years (4). FDA-approved 41 drugs provide safe alternatives only in the case where at least modest antiviral activity can be 42 achieved. Accordingly, several drugs are being tested in numerous clinical trials (5) including 43 remdesivir, lopinavir, and chloroquine (6). 44In this study, we screened a panel of FDA-approved drugs to identify antiviral drug candidates 45 for the treatment of COVID-19 and suggest the identified drug candidates may be considered for 46 therapeutic development. 48 Results and Discussion 49We screened approximately 3,000 FDA-and IND-approved drug library against SARS-CoV to 50 identify antiviral drug candidates (manuscript in preparation). Since the SARS-CoV and SARS-51 CoV-2 are very similar (79.5% sequence identity) (1), the drugs which show antiviral activity 52 against SARS-CoV are expected to show similar extent of antiviral activity against SARS-CoV-2. 53A total of 35 drugs were selected from the earlier SARS-CoV screening results. In addition, 13 54 drugs were included based on recommendations from infectious diseases specialists (Table 1). 55For screening experiments, Vero cells were used and each drug was added to the cells prior to 56 the virus infection. At 24 h after the infection, the infected cells were scored by 57 immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2. 58The confocal microscope images of both viral N protein and cell nuclei were analyzed using our 59 in-house Image Mining (IM) software and the dose-response curve (DRC) for each drug was 60 generated (Figure 1). 61 on June 9, 2020 by guest http://aac.asm.org/ Downloaded from Chloroquine, lopinavir, and remdesivir were used as reference drugs with IC 50 values of 9.12, 62 7.28, and 11.41 µM, respectively ( Figure 1A). Among the 48 drugs that were evaluated in our 63 study, 24 drugs showed potential antiviral activities against SARS-CoV-2 with IC 50 values in 64 be...

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LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50≤0.5 µM), and was posited to exploit the physiological difference between static viral membranes and biogenic cellular membranes. We now report on the molecular mechanism that results in LJ001's specific inhibition of virus-cell fusion.The antiviral activity of LJ001 was light-dependent, required the presence of molecular oxygen, and was reversed by singlet oxygen (1O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated 1O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. 1O2-mediated allylic hydroxylation of unsaturated phospholipids leads to a trans-isomerization of the double bond and concurrent formation of a hydroxyl group in the middle of the hydrophobic lipid bilayer. LJ001-induced 1O2-mediated lipid oxidation negatively impacts on the biophysical properties of viral membranes (membrane curvature and fluidity) critical for productive virus-cell membrane fusion. LJ001 did not mediate any apparent damage on biogenic cellular membranes, likely due to multiple endogenous cytoprotection mechanisms against phospholipid hydroperoxides.Based on our understanding of LJ001's mechanism of action, we designed a new class of membrane-intercalating photosensitizers to overcome LJ001's limitations for use as an in vivo antiviral agent. Structure activity relationship (SAR) studies led to a novel class of compounds (oxazolidine-2,4-dithiones) with (1) 100-fold improved in vitro potency (IC50<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of 1O2 generation), and (4) 10–100-fold improved bioavailability. Candidate compounds in our new series moderately but significantly (p≤0.01) delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV). The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.

Allowing the viewing of animated cartoons by pediatric surgical patients is a very effective method to alleviate preoperative anxiety. Our study suggests that this intervention is an inexpensive, easy to administer, and comprehensive method for anxiety reduction in the pediatric surgical population.

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