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Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern

Frasson et al., Journal of Molecular Cell Biology. doi:10.1093/jmcb/mjae004

Feb 2024

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N-acetylcysteine

14th treatment shown to reduce risk in February 2021, now with p = 0.000028 from 24 studies, recognized in 3 countries.

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In Vitro study showing that inhibition of host cell factors rather than viral elements may prevent emergence of SARS-CoV-2 variants resistant to current drugs. Authors identified host genes/proteins commonly required for infection by major variants using CRISPR screening of infected human lung cells. Targeting hits RIPK4, SLC7A11 or MASTL with existing drugs blocked variant replication and virus-induced cytotoxicity. Mechanistic studies revealed variants rapidly induce reactive oxygen species (ROS), while ROS suppression with antioxidants (NAC/GSH) potently blocked infection. NAC treatment in infected humanized mice reduced lung viral load.

9 preclinical studies support the efficacy of N-acetylcysteine for COVID-19:

1 In Silico study1

7 In Vitro studies2-8

1 In Vivo animal study4

N-acetylcysteine shows dose-dependent inhibition of SARS-CoV-23,6,8, shows anti-inflammatory and immunomodulatory effects against SARS-CoV-2-induced immune responses in combination with bromelain5, suppressed virus-induced reactive oxygen species and blocked viral replication in a humanized mouse model and in human lung cells4, and may limit COVID-19 induced cardiac damage by boosting cellular antioxidant defenses and potentially mitigating the oxidative stress caused by spike protein-induced ROS production in cardiac fibroblasts9. NAC may be beneficial for COVID-19 by replenishing glutathione stores and reinforcing the glutathione peroxidase-4 pathway to inhibit ferroptosis, an oxidative stress-induced cell death pathway implicated in COVID-1910. NAC reinforces glutathione levels, reduces ROS, and minimizes ferroptosis and cytokine storm11.

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1. Agamah et al., Network-based multi-omics-disease-drug associations reveal drug repurposing candidates for COVID-19 disease phases, ScienceOpen, doi:10.58647/DRUGARXIV.PR000010.v1.scienceopen.com, doi.org.

2. Van Tin et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.com, doi.org.

3. Chaopreecha et al., Proteomic Analysis Identifies the Glutathione Synthesizing Enzyme Gclc as an Andrographolide Target and a Protective Factor Against Sars-Cov-2 Infection, Elsevier BV, doi:10.2139/ssrn.4876852.ssrn.com, doi.org.

4. Frasson et al., Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern, Journal of Molecular Cell Biology. doi:10.1093/jmcb/mjae004, academic.oup.com/jmcb/advance-article/doi/10.1093/jmcb/mjae004/7596546.oup.com.

5. Ferreira et al., Taming the SARS-CoV-2-mediated proinflammatory response with BromAc®, Frontiers in Immunology, doi:10.3389/fimmu.2023.1308477.frontiersin.org, doi.org.

6. La Maestra et al., Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment, Cells, doi:10.3390/cells11203313.mdpi.com, doi.org.

7. Goc et al., Inhibitory effects of specific combination of natural compounds against SARS-CoV-2 and its Alpha, Beta, Gamma, Delta, Kappa, and Mu variants, European Journal of Microbiology and Immunology, doi:10.1556/1886.2021.00022.akjournals.com, doi.org.

8. Akhter et al., The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2, Viruses, doi:10.3390/v13030425.mdpi.com, doi.org.

9. Van Tin (B) et al., Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-κB Signaling, Cells, doi:10.3390/cells13161331.mdpi.com, doi.org.

10. Yuan et al., The role of cell death in SARS-CoV-2 infection, Signal Transduction and Targeted Therapy, doi:10.1038/s41392-023-01580-8.nature.com, doi.org.

11. Xie et al., The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death, Cellular & Molecular Biology Letters, doi:10.1186/s11658-024-00659-6.biomedcentral.com, doi.org.

Frasson et al., 1 Feb 2024, peer-reviewed, 16 authors.

This Paper N-acetylcys..All

Abstract: Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern A N U SC RI PT 1 Department of Molecular Medicine, University of Padua, Padua 35121, Italy 2 Department of Biology, Armenise/Harvard Pluripotent Stem Cell Biology Laboratory, University of Padua, Padua 35131, Italy 3 Department. of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35128, Italy 4 Veneto Institute of Oncology IOV-IRCCS, Padua 35128, Italy 5 Department of Comparative Biomedicine and Food Science, University of Padua, Padua 35020, Italy 6 Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, Pozzuoli 80078, Italy 7 Department of Translational Medicine, Federico II University, Naples 80138, Italy 8 School for Advanced Studies, Genomics and Experimental Medicine Program, University of Naples “Federico II”, Naples 80138, Italy 9 Microbiology and Virology Unit, Padua University Hospital, Padua 35128, Italy † O RI G IN A L U N ED IT ED M These authors contributed equally to this work. * Correspondence to: Sara N. Richter, E-mail: sara.richter@unipd.it; Marco Montagner, Email: marco.montagner@unipd.it; Graziano Martello, E-mail: graziano.martello@unipd.it © The Author(s) 2024. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Ilaria Frasson1,†, Linda Diamante1,2,†, Manuela Zangrossi1,†, Elena Carbognin2, Anna Dalla Pietà3, Alessandro Penna3, Antonio Rosato3,4, Ranieri Verin5, Filippo Torrigiani5, Cristiano Salata1, Marìa Paula Dizanzo1, Lorenzo Vaccaro6,7, Davide Cacchiarelli6,7,8, Sara N. Richter1,9,*, Marco Montagner1,*, Graziano Martello2,* Abstract The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants, some of which are resistant to vaccines and drugs targeting viral elements. Targeting host dependency factors, e.g. cellular proteins required for viral replication, would variants induce conserved cellular responses and exploit the same core host factors. To this end, we compared three variants of concern and found that the host transcriptional response was conserved, differing only in kinetics and magnitude. PT Through CRISPR screening, we identified host genes required for infection by each RI variant. Most of the genes were shared by multiple variants. We validated our hits with small molecules and repurposed Food and Drug Administration-approved drugs. SC All the drugs were highly active against all the variants tested, including new variants that emerged during the study (Delta and Omicron). Mechanistically, we identified U reactive oxygen species production as a key step in early virus replication. N Antioxidants such as N-acetyl cysteine (NAC) were effective against all the variants A in both human lung cells and a humanised mouse model. Our study supports the use M of available antioxidant drugs, such as NAC, as a general and effective..

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