Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19
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Abstract
The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov–Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.
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SciScore for 10.1101/2020.10.23.352666: (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
Experimental Models: Cell Lines Sentences Resources SARS-CoV-2 gene expression signatures: Blanco-Melo et al. generated a differential gene expression signature using RNA-seq on human adenocarcinomic alveolar basal epithelial cells infected with SARS-CoV-2 propagated from Vero E6 cells (GSE147507)24. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Paired-end reads were mapped to the hg19 human reference genome using Salmon (v.1.2.0) and assigned Ensembl genes. Salmonsuggested: (Salmon, RRID:SCR_017036)Raw counts were used as inputs to DESeq2 (v. DESeq2suggested: (DESeq, RRID:SCR_000154)Principal components were … SciScore for 10.1101/2020.10.23.352666: (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
Experimental Models: Cell Lines Sentences Resources SARS-CoV-2 gene expression signatures: Blanco-Melo et al. generated a differential gene expression signature using RNA-seq on human adenocarcinomic alveolar basal epithelial cells infected with SARS-CoV-2 propagated from Vero E6 cells (GSE147507)24. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Paired-end reads were mapped to the hg19 human reference genome using Salmon (v.1.2.0) and assigned Ensembl genes. Salmonsuggested: (Salmon, RRID:SCR_017036)Raw counts were used as inputs to DESeq2 (v. DESeq2suggested: (DESeq, RRID:SCR_000154)Principal components were generated using the DESeq2 function (Figure S2), and heat maps were generated using the Bioconductor package pheatmap (v.1.0.12) using the rlog-transformed counts (Figure S3). Bioconductorsuggested: (Bioconductor, RRID:SCR_006442)pheatmapsuggested: (pheatmap, RRID:SCR_016418)The 50 Hallmark Gene Sets used in the GSEA analysis were downloaded from MSigDB Signatures database29,47. MSigDB Signaturessuggested: NoneFor GO (Gene Ontology) terms, identification of enriched biological themes was performed using the DAVID database48. DAVIDsuggested: (DAVID, RRID:SCR_001881)For significance values of the number of drugs reversing multiple signatures, we constructed distributions of the common reversal (reversing two of three signatures) and the consensus reversal (reversing three of three signatures) by randomly sampling the same number of drug profiles for each signature from CMap. CMapsuggested: (CMAP, RRID:SCR_009034)An individual Seurat object for each sample was generated using Seurat v.3. Seuratsuggested: (SEURAT, RRID:SCR_007322)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: We detected the following sentences addressing limitations in the study:There are several limitations of our approach that should be recognized. Data generated from cell lines (both the ALV and EXP signatures) might not accurately represent the biological changes and responses in human infection. Moreover, although the BALF signature was generated from fluid recovered from lavage of infected human tissues, this primary response data was aggregated from a very limited sample size (2 cases and 3 controls). Gathering samples from a larger number of patients should generate a more robust gene expression signature and better inform therapeutic predictions. Furthermore, the drug profiles from CMap were generated from cell line data; drug data generated from more relevant tissue cultures (e.g. lung tissue) may generate more appropriate comparisons. The drug development response for SARS-CoV-2 / COVID-19 is rapidly developing. One drug, remdesivir, recently received FDA approval for the treatment of COVID-19, and numerous other drugs are being actively explored for possible therapeutic value in COVID-19 cases. Utilizing a diverse set of transcriptomic SARS-CoV-2 signatures, our drug repositioning pipeline identified 25 therapeutic candidates. Validation experiments revealed antiviral activity for 11 of 16 drug hits. Further clinical investigation into these drug hits as well as potential combination therapies is warranted.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04371640 Withdrawn Sirolimus in COVID-19 Phase 1 NCT04341675 Recruiting Sirolimus Treatment in Hospitalized Patients With COVID-19 P… NCT04461340 Recruiting Efficacy and Safety of Sirolimus in COVID-19 Infection NCT04412785 Recruiting Cyclosporine in Patients With Moderate COVID-19 NCT04392531 Recruiting Clinical Trial to Assess Efficacy of cYclosporine Plus Stand… NCT04558021 Recruiting A Study To Evaluate The Efficacy And Safety Of a Novel Niclo… NCT04465695 Recruiting Dual Therapy With Interferon Beta-1b and Clofazimine for COV… 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.
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