Journal
SCIENCE
Volume 371, Issue 6532, Pages 926-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abf4058
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Funding
- Defense Advanced Research Projects Agency [HR0011-19-2-0020]
- CRIP (Center for Research for Influenza Pathogenesis), a NIAID [HHSN272201400008C]
- NIAID [U19AI135972]
- DoD [W81XWH20-1-0270]
- JPB Foundation
- Open Philanthropy Project [2020-215611 (5384)]
- Huffington Foundation
- NIH [U19AI135972, P50AI150476, U19AI135990, R01AI143292, R01AI120694, P01A1063302, R01AI122747, 1R01CA221969, 1R01CA244550, F32CA239333]
- Laboratory for Genomics Research (LGR) [133122P]
- Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases [ANR-10-LABX-62-IBEID]
- FastGrants COVID19 grant from the Emergent Ventures program at the Mercatus Center of George Mason University
- F. Hoffmann-La Roche
- Vir Biotechnology
- Roddenberry Foundation
- Swiss National Foundation (SNF) Early Postdoc.Mobility fellowship [P2GEP3_184202]
- Swiss National Science Foundation (SNF) [P2GEP3_184202] Funding Source: Swiss National Science Foundation (SNF)
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The study revealed that plitidepsin possesses potent antiviral activity against SARS-CoV-2, more effective than the approved drug remdesivir. By inhibiting the eukaryotic translation elongation factor 1A, plitidepsin can significantly reduce viral replication of SARS-CoV-2 in the lungs of mice, making it a promising candidate for COVID-19 treatment.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
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