RT Journal Article
SR Electronic
T1 Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.27.270819
DO 10.1101/2020.08.27.270819
A1 Ersin Akinci
A1 Minsun Cha
A1 Lin Lin
A1 Grace Yeo
A1 Marisa C. Hamilton
A1 Callie J. Donahue
A1 Heysol C. Bermudez-Cabrera
A1 Larissa C. Zanetti
A1 Maggie Chen
A1 Sammy A. Barkal
A1 Benyapa Khowpinitchai
A1 Nam Chu
A1 Minja Velimirovic
A1 Rikita Jodhani
A1 James D. Fife
A1 Miha Sovrovic
A1 Philip A. Cole
A1 Robert A. Davey
A1 Christopher A. Cassa
A1 Richard I. Sherwood
YR 2020
UL http://biorxiv.org/content/early/2020/08/28/2020.08.27.270819.abstract
AB 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 illness1. Prior clinical studies have identified adverse events1,2, and remdesivir has been shown to inhibit mitochondrial RNA polymerase in biochemical experiments7, 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 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.Competing Interest StatementThe authors declare competing interests: a patent application has been filed on this work.