Elucidating host cell response pathways and repurposing therapeutics for SARS-CoV-2 and other coronaviruses using gene expression profiles of chemical and genetic perturbations
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Abstract
COVID-19 is an ongoing pandemic that has been causing devastation across the globe for over 2 years. Although there are multiple vaccines that can prevent severe symptoms, effective COVID-19 therapeutics are still of importance. Using our proprietary in silico SMarTR™ engine, we screened more than 22,000 unique compounds represented by over half a million gene expression profiles to uncover compounds that can be repurposed for SARS-CoV-2 and other coronaviruses in a timely and cost-efficient manner. We then tested 13 compounds in vitro and found three with potency against SARS-CoV-2 with reasonable cytotoxicity. Bortezomib and homoharringtonine are some of the most promising hits with IC 50 of 1.39 μM and 0.16 μM, respectively for SARS-CoV-2. Tanespimycin and homoharringtonine were effective against the common cold coronaviruses. In-depth analysis highlighted proteasome, ribosome, and heat shock pathways as key targets in modulating host responses during viral infection. Further studies of these pathways and compounds have provided novel and impactful insights into SARS-CoV-2 biology and host responses that could be further leveraged for COVID-19 therapeutics development.
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SciScore for 10.1101/2022.04.18.488682: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Subsequently, cells were stained with anti-SARS-CoV-2 Nucleocapsid (N) primary antibody, a 488-conjugated goat anti-rabbit IgG secondary antibody and Hoechst 33342. anti-SARS-CoV-2suggested: Noneanti-rabbit IgGsuggested: NoneExperimental Models: Cell Lines Sentences Resources Anti-HCoV-229E and HCoV-OC43 compound testing Human lung fibroblast MRC5 cells were cultured in a 96-well plate at 10,000 cells/well in EMEM+10% FBS overnight. MRC5suggested: NoneSoftware and Algorithms Sentences Resources RNAseq data were processed using Salmon algorithm which was adapted to Auransa’s internal pipelines [22]. Salmonsugges…SciScore for 10.1101/2022.04.18.488682: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Subsequently, cells were stained with anti-SARS-CoV-2 Nucleocapsid (N) primary antibody, a 488-conjugated goat anti-rabbit IgG secondary antibody and Hoechst 33342. anti-SARS-CoV-2suggested: Noneanti-rabbit IgGsuggested: NoneExperimental Models: Cell Lines Sentences Resources Anti-HCoV-229E and HCoV-OC43 compound testing Human lung fibroblast MRC5 cells were cultured in a 96-well plate at 10,000 cells/well in EMEM+10% FBS overnight. MRC5suggested: NoneSoftware and Algorithms Sentences Resources RNAseq data were processed using Salmon algorithm which was adapted to Auransa’s internal pipelines [22]. Salmonsuggested: (Salmon, RRID:SCR_017036)Data analysis was performed using GraphPad Prism 8, and SI calculated as the ratio of CC50 to EC50. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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