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<p>SARS-CoV-2 is a positive-sense RNA virus that was responsible for the devastating COVID-19 pandemic. Although the current disease burden is less severe, there are limited treatment options, and a looming threat of the emergence of variants and future pandemics. To address these challenges, we performed genome-wide CRISPR knockout screens in a novel human lung cell line NCI-H23<sup>ACE2</sup>, as well as in HEK293T<sup>ACE2</sup> cells, with SARS-CoV-2 Wuhan strain, and identified several host-dependency factors including NRAS, KAT5, HTR3E and GNL3L. Drugs targeting some of these dependency factors, donepezil, dH-ergocristine, trametinib and sorafenib, showed effective pan-coronaviral inhibition in cell lines. Trametinib also showed inhibition of SARS-CoV-2 Delta variant in primary human airway tissue model (ALI). We also demonstrate that SARS-CoV-2 inhibits IFN-β induction through an NRAS/Raf/MEK/ERK signaling pathway dependent mechanism. Our study highlights the efficiency of a bilateral approach of gene silencing and antiviral screening to identify host-dependency factors and effective antivirals.</p>

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Genome-wide screening identifies unique host-directed drugs and pro-viral signalling pathways for SARS-CoV-2

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月22日

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  • Juveriya Qamar Khan,
  • Karthic Rajamanickam,
  • Frederick S. Vizeacoumar,
  • Mahrokh Balouchi,
  • Yue Zhang,
  • Hussain Elhasasna,
  • Megha Rohamare,
  • He Dong,
  • Kathleen Glover,
  • Tristan Anderson-Woodsworth,
  • Kalpana K. Bhanumathy,
  • Jocelyne Lew,
  • Franco J. Vizeacoumar,
  • Darryl Falzarano,
  • Anil Kumar,
  • Joyce A. Wilson

摘要

SARS-CoV-2 is a positive-sense RNA virus that was responsible for the devastating COVID-19 pandemic. Although the current disease burden is less severe, there are limited treatment options, and a looming threat of the emergence of variants and future pandemics. To address these challenges, we performed genome-wide CRISPR knockout screens in a novel human lung cell line NCI-H23ACE2, as well as in HEK293TACE2 cells, with SARS-CoV-2 Wuhan strain, and identified several host-dependency factors including NRAS, KAT5, HTR3E and GNL3L. Drugs targeting some of these dependency factors, donepezil, dH-ergocristine, trametinib and sorafenib, showed effective pan-coronaviral inhibition in cell lines. Trametinib also showed inhibition of SARS-CoV-2 Delta variant in primary human airway tissue model (ALI). We also demonstrate that SARS-CoV-2 inhibits IFN-β induction through an NRAS/Raf/MEK/ERK signaling pathway dependent mechanism. Our study highlights the efficiency of a bilateral approach of gene silencing and antiviral screening to identify host-dependency factors and effective antivirals.