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| Status |
Public on Feb 02, 2021 |
| Title |
Clofazimine is a broad-spectrum coronavirus inhibitor that antagonizes SARS-CoV-2 replication in primary human cell culture and hamsters |
| Organisms |
Homo sapiens; Mesocricetus auratus; Severe acute respiratory syndrome coronavirus 2 |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
COVID-19 is the third outbreak of zoonotic coronavirus (CoV) of the century after the epidemic Severe acute respiratory syndrome CoV (SARS-CoV) in 2003 and Middle East respiratory syndrome CoV (MERS-CoV) in 2012. Treatment options for CoVs are largely lacking. Here, we show that clofazimine, an anti-leprosy drug with favorable safety and pharmacokinetics profile, possesses pan-coronaviral inhibitory activity, and can antagonize SARS-CoV-2 replication in multiple in vitro systems, including the human embryonic stem cell-derived cardiomyocytes and ex vivo lung cultures. The FDA-approved molecule was found to inhibit multiple steps of viral replication, suggesting polypharmacology is likely underlying its antiviral activity. In a hamster model of SARS-CoV-2 pathogenesis, prophylactic and therapeutic administration of clofazimine significantly reduced lung viral load and fecal viral shedding, as well as reversal of cytokine storm. Additionally, clofazimine exhibited antiviral drug synergy when administered with remdesivir. Since clofazimine is orally bioavailable and has a comparatively low manufacturing cost, it is an attractive clinical candidate for outpatient treatment and remdesivir-based combinatorial therapy for hospitalized COVID-19 patients, particularly in developing countries. Taken together, our data provide evidence that clofazimine may prove effective against current pandemic SARS-CoV-2, endemic MERS-CoV in the Middle East, and, possibly most importantly, emerging CoV of the future.
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| Overall design |
For experiment on Caco-2 cells, cells were infected with or without SARS-CoV-2 (MOI=4) and treated with clofazimine (10 µM) or DMSO vehicle control for 3hours or 6 hours. For the experiment on golden hamsters, we delivered clofazimine through oral route utilizing corn oil as vehicle. Prophylactic treatment through oral administration of clofazimine was given at -3, -2 and -1 dpi (days post infection) (25 mg/kg/day), followed by virus challenge at 0dpi through intranasal route; therapeutic post-exposure administration of clofazimine was performed at 1, 2, and 3 dpi applying the same drug dosage and virus inoculum. Lung tissues were collected at 4dpi for prophylactic and therapeutic groups. For uninfected group, clofazimine was given for 3 consecutive days and lung tissues were collected on day 4.
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| Contributor(s) |
Meng X, Yuan S, Sun R, Chanda SK, Yuen K |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Dec 08, 2020 |
| Last update date |
Feb 02, 2021 |
| Contact name |
Xiangzhi Meng |
| E-mail(s) |
mengxiangzhi919@gmail.com
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| Organization name |
The University of Hong Kong
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| Street address |
21 Sassoon Road
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| City |
Hong Kong SAR |
| ZIP/Postal code |
000000 |
| Country |
Hong Kong |
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| Platforms (4)
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| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
| GPL28997 |
Illumina NovaSeq 6000 (Mesocricetus auratus) |
| GPL29320 |
Illumina NovaSeq 6000 (Homo sapiens; Severe acute respiratory syndrome coronavirus 2) |
| GPL29486 |
Illumina NovaSeq 6000 (Mesocricetus auratus; Severe acute respiratory syndrome coronavirus 2) |
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| Samples (39)
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| Relations |
| BioProject |
PRJNA683662 |
| SRA |
SRP297170 |
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