Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics

Akinci, Ersin; Cha, Minsun; Lin, Lin; Yeo, Grace Hui Ting; Hamilton, Marisa C; Donahue, Callie J.; Bermudez-Cabrera, Heysol C; Zanetti, Larissa C; Chen, Maggie; Barkal, Sammy; Khowpinitchai, Benyapa; Chu, Nam; Velimirovic, Minja; Jodhani, Rikita; Fife, James D.; Sovrovic, Miha; Cole, Philip A.; Davey, Robert A.; Cassa, Christopher A.; Sherwood, Richard I.

doi:10.1101/2020.08.27.270819

Cited by 23 publications

(20 citation statements)

References 67 publications

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“…Additional biochemical assays showed the active triphosphate metabolite GS-443902 was a poor substrate for mitochondrial DNA and RNA polymerases, even when tested at supraphysiological concentrations of 50 and 500 μM, respectively. A recent paper reported the effects of RDV on cellular toxicity through a transcriptomic analysis, and reported effects of RDV on mitochondrial function ( 26 ). However, it is not clear whether the results were due to specific mitochondrial toxicity or general cellular toxicity.…”

Section: Discussionmentioning

confidence: 99%

Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent

Barauskas

Kim

et al. 2021

Antimicrob Agents Chemother

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Remdesivir (RDV, GS-5734), the first FDA-approved antiviral for the treatment of COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. It is intracellularly metabolized into the active triphosphate form, which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. RDV has broad-spectrum activity against members of the coronavirus family such as SARS-CoV-2, SARS-CoV, and MERS-CoV, as well as filoviruses and paramyxoviruses. To assess potential for off-target toxicity, RDV was evaluated in a set of cellular and biochemical assays. Cytotoxicity was evaluated in a set of relevant human cell lines and primary cells. In addition, RDV was evaluated for mitochondrial toxicity under aerobic and anaerobic metabolic conditions, and for the effects on mitochondrial DNA content, mitochondrial protein synthesis, cellular respiration, and induction of reactive oxygen species. Lastly, the active 5’-triphosphate metabolite of RDV, GS-443902, was evaluated for potential interaction with human DNA and RNA polymerases. Among all of the human cells tested under 5-14 days of continuous exposure, RDV’s CC50 values ranged from 1.7 to >20 μM, resulting in selectivity indices (SI, CC50/EC50) from >170 to 20,000, with respect to RDV anti-SARS-CoV-2 activity (EC50 of 9.9 nM in human airway epithelial cells). Overall, the cellular and biochemical assays demonstrated a low potential of RDV for off-target toxicity including mitochondria-specific toxicity, consistent with the reported clinical safety profile.

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Section: Discussionmentioning

confidence: 99%

Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent

Barauskas

Kim

et al. 2021

Antimicrob Agents Chemother

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“…Recent research reported that remdesivir was superior to placebo in shortening the time to recovery of hospitalized COVID-19 patients [96]. Whereas, in vitro experiments showed that Remdesivir and its metabolites were cytotoxic and mitochondrial toxic to a variety of cells, especially hepatocytes [97]. In a trial comparing remdesivir treatment for either 5 or 10 days, severe but not immediately life-threatening ALT/AST elevations were reported in 4-6% of patients and life-threatening AST/ALT elevations in 2-3% of patients [98].…”

Section: Drug-induced Liver Injurymentioning

confidence: 99%

COVID-19-associated liver injury: from bedside to bench

Ding

Xie

et al. 2021

J Gastroenterol

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The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a global challenge since December 2019. Although most patients with COVID-19 exhibit mild clinical manifestations, in approximately 5% of these patients, the disease eventually progresses to severe lung injury or even multiorgan dysfunction. This situation represents various challenges to hepatology. In the context of liver injury in patients with COVID-19, several key problems need to be solved. For instance, it is important to determine whether SARS-CoV-2 can directly invade liver, especially when ACE2 appears to be negligibly expressed on hepatocytes. In addition, the mechanisms underlying liver dysfunction in COVID-19 patients are not fully understood, which are likely multifactorial and related to hyperinflammation, dysregulated immune responses, abnormal coagulation and drugs. Here, we systematically describe the potential pathogenesis of COVID-19-associated liver injury and propose several hypotheses about its etiopathogenesis.

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“…Two recent studies have utilized this method in both Vero cells and hepatoma cells and identified host factors ACE2, the protease Cathepsin L, and TMEM106B to play a crucial role in viral infection ( Wang et al., 2020b ; Wei et al., 2020 ). Another study utilized genome-wide CRISPR screens to elucidate the cytotoxicity pathways of remdesivir, a drug that is now commonly administered to SARS-CoV-2 patients ( Akinci et al., 2020 ). These insights gathered from classical cell lines, await confirmation in more physiologically relevant systems, such as organoids.…”

Section: The Crispr Search For Host Factors Of Sars-cov-2 Entrymentioning

confidence: 99%

The Organoid Platform: Promises and Challenges as Tools in the Fight against COVID-19

Geurts¹,

Vaart²,

Beumer³

2021

Stem Cell Reports

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Many pathogenic viruses that affect man display species specificity, limiting the use of animal models. Studying viral biology and identifying potential treatments therefore benefits from the development of in vitro cell systems that closely mimic human physiology. In the current COVID-19 pandemic, rapid scientific insights are of the utmost importance to limit its impact on public health and society. Organoids are emerging as versatile tools to progress the understanding of SARS-CoV-2 biology and to aid in the quest for novel treatments.

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Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics

Cited by 23 publications

References 67 publications

Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent

Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent

COVID-19-associated liver injury: from bedside to bench

The Organoid Platform: Promises and Challenges as Tools in the Fight against COVID-19

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