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Synthetic lethality-based prediction of anti-SARS-CoV-2 targets

Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners o...

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Autores principales: Pal, Lipika R., Cheng, Kuoyuan, Nair, Nishanth Ulhas, Martin-Sancho, Laura, Sinha, Sanju, Pu, Yuan, Riva, Laura, Yin, Xin, Schischlik, Fiorella, Lee, Joo Sang, Chanda, Sumit K., Ruppin, Eytan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044693/
https://www.ncbi.nlm.nih.gov/pubmed/35502318
http://dx.doi.org/10.1016/j.isci.2022.104311
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author Pal, Lipika R.
Cheng, Kuoyuan
Nair, Nishanth Ulhas
Martin-Sancho, Laura
Sinha, Sanju
Pu, Yuan
Riva, Laura
Yin, Xin
Schischlik, Fiorella
Lee, Joo Sang
Chanda, Sumit K.
Ruppin, Eytan
author_facet Pal, Lipika R.
Cheng, Kuoyuan
Nair, Nishanth Ulhas
Martin-Sancho, Laura
Sinha, Sanju
Pu, Yuan
Riva, Laura
Yin, Xin
Schischlik, Fiorella
Lee, Joo Sang
Chanda, Sumit K.
Ruppin, Eytan
author_sort Pal, Lipika R.
collection PubMed
description Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDL with altered host genes. The predicted SL/SDL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. We further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming noninfected healthy cells.
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spelling pubmed-90446932022-04-28 Synthetic lethality-based prediction of anti-SARS-CoV-2 targets Pal, Lipika R. Cheng, Kuoyuan Nair, Nishanth Ulhas Martin-Sancho, Laura Sinha, Sanju Pu, Yuan Riva, Laura Yin, Xin Schischlik, Fiorella Lee, Joo Sang Chanda, Sumit K. Ruppin, Eytan iScience Article Novel strategies are needed to identify drug targets and treatments for the COVID-19 pandemic. The altered gene expression of virus-infected host cells provides an opportunity to specifically inhibit viral propagation via targeting the synthetic lethal and synthetic dosage lethal (SL/SDL) partners of such altered host genes. Pursuing this disparate antiviral strategy, here we comprehensively analyzed multiple in vitro and in vivo bulk and single-cell RNA-sequencing datasets of SARS-CoV-2 infection to predict clinically relevant candidate antiviral targets that are SL/SDL with altered host genes. The predicted SL/SDL-based targets are highly enriched for infected cell inhibiting genes reported in four SARS-CoV-2 CRISPR-Cas9 genome-wide genetic screens. We further selected a focused subset of 26 genes that we experimentally tested in a targeted siRNA screen using human Caco-2 cells. Notably, as predicted, knocking down these targets reduced viral replication and cell viability only under the infected condition without harming noninfected healthy cells. Elsevier 2022-04-27 /pmc/articles/PMC9044693/ /pubmed/35502318 http://dx.doi.org/10.1016/j.isci.2022.104311 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Pal, Lipika R.
Cheng, Kuoyuan
Nair, Nishanth Ulhas
Martin-Sancho, Laura
Sinha, Sanju
Pu, Yuan
Riva, Laura
Yin, Xin
Schischlik, Fiorella
Lee, Joo Sang
Chanda, Sumit K.
Ruppin, Eytan
Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title_full Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title_fullStr Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title_full_unstemmed Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title_short Synthetic lethality-based prediction of anti-SARS-CoV-2 targets
title_sort synthetic lethality-based prediction of anti-sars-cov-2 targets
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9044693/
https://www.ncbi.nlm.nih.gov/pubmed/35502318
http://dx.doi.org/10.1016/j.isci.2022.104311
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