Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics
et al., bioRxiv, doi:10.1101/2020.08.27.270819, Aug 2020
In vitro study analyzing the cytotoxicity pathways of remdesivir using genome-wide CRISPR-Cas9 screening and RNA sequencing. Remdesivir treatment significantly repressed nuclear genes encoding mitochondrial respiratory complexes, leading to decreased ATP production and mitochondrial oxidation.
Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov, Arch show increased risk of liver injury, Negru, Cheng, Mohammed, Kwok, Zhu show increased risk of cardiac disorders, and Kwok, Merches, Akinci, Tang, Bagheri show increased risk of mitochondrial toxicity with remdesivir.
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Akinci et al., 28 Aug 2020, USA, preprint, 20 authors.
Contact: rsherwood@rics.bwh.harvard.edu (corresponding author).
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: ## Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics
Ersin Akinci 1,2,* , Minsun Cha 1,* , Lin Lin 3,* , Grace Yeo 4,5,* , Marisa C. Hamilton 1,* , Callie J. Donahue 6,# , Heysol C. Bermudez-Cabrera 1,# , Larissa C. Zanetti 1,7,# , Maggie Chen 1,8,# , Sammy A. Barkal 1,# , Benyapa Khowpinitchai 1,# , Nam Chu 1,9 , Minja Velimirovic 1,10 , Rikita Jodhani 1 , James D. Fife 1 , Miha Sovrovic 1 , Philip A. Cole 1,9 , Robert A. Davey 6 , Christopher A. Cassa 1 , and Richard I. Sherwood 1,3,
1 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 2 Department of Agricultural Biotechnology, Faculty of Agriculture, Akdeniz University, Antalya, 07070, Turkey 3
Hubrecht Institute, 3584 CT Utrecht, the Netherlands
4 Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 5
Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
6 Department of Microbiology, National Emerging Infectious Disease Laboratories, Boston University Medical Campus, Boston, MA 02118, USA 7 Hospital Israelita Albert Einstein, São Paulo, SP 05652-900, Brazil
8 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138
9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115
Centre Hospitalier Universitaire de Québec Research Center-Université Laval, Québec, Québec G1V 4G2, Canada
10
The adenosine analogue remdesivir has emerged as a frontline antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness 1 . Prior clinical studies have identified adverse events 1,2 , and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments 7 , yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPRCas9 screening and RNA sequencing, we show that remdesivir treatment leads to a repression of mitochondrial respiratory activity, and we identify five genes whose loss significantly reduces remdesivir cytotoxicity. In particular, we show that loss of the mitochondrial nucleoside transporter SLC29A3 mitigates remdesivir toxicity without a commensurate decrease in SARS-CoV-2 antiviral potency and that the mitochondrial adenylate kinase AK2 is a remdesivir kinase required for remdesivir efficacy and toxicity. This work elucidates the cellular mechanisms of remdesivir metabolism and provides a candidate gene target to reduce remdesivir cytotoxicity.
DRAFT Corresponding author: R.I.S. * These authors contributed equally to this work # These authors contributed equally to this work dosing or treatment earlier in disease progression as has been shown for other antiviral drugs such as oseltamivir (Tamiflu) 1,5,7,9-11 . One possible mode of toxicity induced by nucleoside analogues is mitochondrial toxicity, as mitochondrial polymerases lack the selectivity of mammalian polymerases to exclude nucleoside analogues. HIV antiviral nucleotide analogues and Hepatitis C virus (HCV) nucleoside analogs induce mitochondrial toxicity with varying levels of severity 12,13 , and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments 14 , albeit at 100-fold lower rates than RdRp.
CRISPR..
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"abstract": "<jats:p>\n The adenosine analogue remdesivir has emerged as a frontline antiviral treatment for SARS-CoV-2, with preliminary evidence that it reduces the duration and severity of illness\n <jats:sup>1</jats:sup>\n . Prior clinical studies have identified adverse events\n <jats:sup>1,2</jats:sup>\n , and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments\n <jats:sup>7</jats:sup>\n , yet little is known about the specific genetic pathways involved in cellular remdesivir metabolism and cytotoxicity. Through genome-wide CRISPR-Cas9 screening and RNA sequencing, we show that remdesivir treatment leads to a repression of mitochondrial respiratory activity, and we identify five genes whose loss significantly reduces remdesivir cytotoxicity. In particular, we show that loss of the mitochondrial nucleoside transporter\n <jats:italic>SLC29A3</jats:italic>\n mitigates remdesivir toxicity without a commensurate decrease in SARS-CoV-2 antiviral potency and that the mitochondrial adenylate kinase\n <jats:italic>AK2</jats:italic>\n is a remdesivir kinase required for remdesivir efficacy and toxicity. This work elucidates the cellular mechanisms of remdesivir metabolism and provides a candidate gene target to reduce remdesivir cytotoxicity.\n </jats:p>",
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