Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV

Stacey L. P. Scroggs; Danielle K. Offerdahl; Dylan P. Flather; Ciera N. Morris; Benjamin L. Kendall; Rebecca M. Broeckel; Paul A. Beare; Marshall E. Bloom

doi:10.3390/v13010008

Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV

Viruses ◽

10.3390/v13010008 ◽

2020 ◽

Vol 13 (1) ◽

pp. 8

Author(s):

Stacey L. P. Scroggs ◽

Danielle K. Offerdahl ◽

Dylan P. Flather ◽

Ciera N. Morris ◽

Benjamin L. Kendall ◽

...

Keyword(s):

Cultured Cells ◽

Respiratory Infections ◽

A549 Cells ◽

Cell Types ◽

Vero Cells ◽

Cellular Toxicity ◽

Antiviral Therapies ◽

Fluoroquinolone Antibiotics ◽

Approved Drugs ◽

Fda Approved Drugs

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 μM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 μM enoxacin and 600 μM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 μM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.

Download Full-text

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

PLoS Pathogens ◽

10.1371/journal.ppat.1009840 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009840

Author(s):

Adam Pickard ◽

Ben C. Calverley ◽

Joan Chang ◽

Richa Garva ◽

Sara Gago ◽

...

Keyword(s):

Drug Repurposing ◽

Cell Types ◽

Vero Cells ◽

Human Cells ◽

Proximal Tubule Cells ◽

Kidney Glomerulus ◽

Infected Cells ◽

Repurposed Drugs ◽

Approved Drugs ◽

Fda Approved Drugs

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

Download Full-text

Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2

10.1101/2020.06.19.161042 ◽

2020 ◽

Cited By ~ 12

Author(s):

Mark Dittmar ◽

Jae Seung Lee ◽

Kanupriya Whig ◽

Elisha Segrist ◽

Minghua Li ◽

...

Keyword(s):

Drug Sensitivity ◽

Drug Repurposing ◽

Vero Cells ◽

Low Ph ◽

Lung Epithelial Cells ◽

Lung Cells ◽

Clinical Implementation ◽

Lung Epithelial ◽

Approved Drugs ◽

Fda Approved Drugs

AbstractThere are an urgent need for antivirals to treat the newly emerged SARS-CoV-2. To identify new candidates we screened a repurposing library of ~3,000 drugs. Screening in Vero cells found few antivirals, while screening in human Huh7.5 cells validated 23 diverse antiviral drugs. Extending our studies to lung epithelial cells, we found that there are major differences in drug sensitivity and entry pathways used by SARS-CoV-2 in these cells. Entry in lung epithelial Calu-3 cells is pH-independent and requires TMPRSS2, while entry in Vero and Huh7.5 cells requires low pH and triggering by acid-dependent endosomal proteases. Moreover, we found 9 drugs are antiviral in lung cells, 7 of which have been tested in humans, and 3 are FDA approved including Cyclosporine which we found is targeting Cyclophilin rather than Calcineurin for its antiviral activity. These antivirals reveal essential host targets and have the potential for rapid clinical implementation.

Download Full-text

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

10.1101/2021.02.14.431162 ◽

2021 ◽

Author(s):

Irene Unterman ◽

Idit Bloch ◽

Simona Cazacu ◽

Gila Kazimirsky ◽

Benjamin P. Berman ◽

...

Keyword(s):

Comparative Genomics ◽

Rett Syndrome ◽

Cell Types ◽

Evolutionary Genomics ◽

Mecp2 Gene ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Human Neural Cell ◽

Eukaryotic Genomes ◽

Inactivating Mutations

AbstractInactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here we use an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1,028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA approved drugs led to three promising candidates, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). We show that each of these compounds has the ability to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appear to act on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.Abstract Figure

Download Full-text

Expanding the MECP2 network using comparative genomics reveals potential therapeutic targets for Rett syndrome

eLife ◽

10.7554/elife.67085 ◽

2021 ◽

Vol 10 ◽

Author(s):

Irene Unterman ◽

Idit Bloch ◽

Simona Cazacu ◽

Gila Kazimirsky ◽

Bruria Ben-Zeev ◽

...

Keyword(s):

Comparative Genomics ◽

Rett Syndrome ◽

Cell Types ◽

Evolutionary Genomics ◽

Mecp2 Gene ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Human Neural Cell ◽

Eukaryotic Genomes ◽

Inactivating Mutations

Inactivating mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene are the main cause of Rett syndrome (RTT). Despite extensive research into MECP2 function, no treatments for RTT are currently available. Here, we used an evolutionary genomics approach to construct an unbiased MECP2 gene network, using 1028 eukaryotic genomes to prioritize proteins with strong co-evolutionary signatures with MECP2. Focusing on proteins targeted by FDA-approved drugs led to three promising targets, two of which were previously linked to MECP2 function (IRAK, KEAP1) and one that was not (EPOR). The drugs targeting these three proteins (Pacritinib, DMF, and EPO) were able to rescue different phenotypes of MECP2 inactivation in cultured human neural cell types, and appeared to converge on Nuclear Factor Kappa B (NF-κB) signaling in inflammation. This study highlights the potential of comparative genomics to accelerate drug discovery, and yields potential new avenues for the treatment of RTT.

Download Full-text

Identification and Characterization of Mefloquine Efficacy against JC Virus In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01614-08 ◽

2009 ◽

Vol 53 (5) ◽

pp. 1840-1849 ◽

Cited By ~ 154

Author(s):

Margot Brickelmaier ◽

Alexey Lugovskoy ◽

Ramya Kartikeyan ◽

Marta M. Reviriego-Mendoza ◽

Norm Allaire ◽

...

Keyword(s):

Viral Entry ◽

Cultured Cells ◽

Jc Virus ◽

Antiviral Treatment ◽

Cell Types ◽

Biologically Active ◽

Biodistribution Data ◽

Approved Drugs

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEΔ), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.

Download Full-text

Discovery of re-purposed drugs that slow SARS-CoV-2 replication in human cells

10.1101/2021.01.31.428851 ◽

2021 ◽

Author(s):

Adam Pickard ◽

Ben C. Calverley ◽

Joan Chang ◽

Richa Garva ◽

Yinhui Lu ◽

...

Keyword(s):

Drug Repurposing ◽

Cell Types ◽

Human Hepatocytes ◽

Human Cells ◽

Proximal Tubule Cells ◽

Kidney Glomerulus ◽

Infected Cells ◽

Repurposed Drugs ◽

Approved Drugs ◽

Fda Approved Drugs

ABSTRACTCOVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, vaccine escape variants might arise leading to a re-emergence of COVID. In anticipation of such a scenario, the identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2- DOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in- line with reported proteinuria and liver damage in patients with COVID-19. We identified 35 drugs that reduced viral replication in Vero and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.

Download Full-text

FDA-Approved Drugs Efavirenz, Tipranavir, and Dasabuvir Inhibit Replication of Multiple Flaviviruses in Vero Cells

Microorganisms ◽

10.3390/microorganisms8040599 ◽

2020 ◽

Vol 8 (4) ◽

pp. 599

Author(s):

Michal Stefanik ◽

James J. Valdes ◽

Fortunatus C. Ezebuo ◽

Jan Haviernik ◽

Ikemefuna C. Uzochukwu ◽

...

Keyword(s):

Human Health ◽

Zika Virus ◽

In Silico ◽

Vero Cells ◽

In Silico Screening ◽

Tick Borne Encephalitis ◽

Vector Borne ◽

Tick Borne Encephalitis Virus ◽

Approved Drugs ◽

Fda Approved Drugs

Vector-borne flaviviruses (VBFs) affect human health worldwide, but no approved drugs are available specifically to treat VBF-associated infections. Here, we performed in silico screening of a library of U.S. Food and Drug Administration-approved antiviral drugs for their interaction with Zika virus proteins. Twelve hit drugs were identified by the docking experiments and tested in cell-based antiviral assay systems. Efavirenz, tipranavir, and dasabuvir at micromolar concentrations were identified to inhibit all VBFs tested; i.e., two representatives of mosquito-borne flaviviruses (Zika and West Nile viruses) and one representative of flaviviruses transmitted by ticks (tick-borne encephalitis virus). The results warrant further research into these drugs, either individually or in combination, as possible pan-flavivirus inhibitors.

Download Full-text