Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium
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Abstract
Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.
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SciScore for 10.1101/2021.06.02.21258223: (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
Software and Algorithms Sentences Resources Low-quality bases (Phred score<20) and adapters were excluded. Phredsuggested: (Phred, RRID:SCR_001017)The gene datasets were analyzed for disease and disorders, molecular and cellular functions, and canonical pathways using Ingenuity Pathway Analysis (IPA) version 60467501 [14]. Ingenuity Pathway Analysissuggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)Mapping SARS-CoV-2-related DEGs to FDA approved/ clinical drugs: To establish a link between SARS-CoV-2-related genes to drugs, we used a commercial drug database of Metacore version 20.3 build 70200 from Clarivate Analytics [15] … SciScore for 10.1101/2021.06.02.21258223: (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
Software and Algorithms Sentences Resources Low-quality bases (Phred score<20) and adapters were excluded. Phredsuggested: (Phred, RRID:SCR_001017)The gene datasets were analyzed for disease and disorders, molecular and cellular functions, and canonical pathways using Ingenuity Pathway Analysis (IPA) version 60467501 [14]. Ingenuity Pathway Analysissuggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)Mapping SARS-CoV-2-related DEGs to FDA approved/ clinical drugs: To establish a link between SARS-CoV-2-related genes to drugs, we used a commercial drug database of Metacore version 20.3 build 70200 from Clarivate Analytics [15] and IPA [14]. Metacoresuggested: (MetaCore, RRID:SCR_008125)Gene prioritization tools utilize mathematical and computational models of disease to filter the original set of genes based on functional similarity (Toppgene tool, https://toppgene.cchmc.org) and, topological features in protein-protein interaction (Toppnet tool, https://toppgene.cchmc.org) to the training genes. Toppgenesuggested: ( ToppGene Suite , RRID:SCR_005726)The Online Mendelian Inheritance in Man (OMIM) database (http://www.omim.org) was searched for genes (training genes) whose inhibition or activation significantly affects the progression of SARS-CoV pathogenesis in human patients. Online Mendelian Inheritance in Mansuggested: NoneResults from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has several limitations. This investigation is based on in vitro RNA-Seq data, resulting in an under-appreciation of significant inter-cellular signaling that may occur differently in the human body. Furthermore, our computational approach is limited as a tool for evaluating drugs to be repurposed because most available computational tools are used for small molecule drugs only. However, given the pressing need for effective targeted therapies for the treatment of COVID-19, further studies are crucially needed to experimentally validate these results and, if promising, rapidly transition to clinical trials.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT02690142 Completed A Study to Investigate the Safety, Tolerability and Pharmaco… NCT03598751 Active, not recruiting Clinical Study of Efficacy and Safety of BCD-085 (Monoclonal… NCT03447704 Active, not recruiting International Multicenter Comparative Randomized Placebo-con… NCT03390101 Active, not recruiting An International Multicenter, Randomized, Double-blind, Plac… NCT04009499 Enrolling by invitation A Study to Assess the Long-term Safety, Tolerability, and Ef… NCT02421172 Completed Efficacy, Safety, and Pharmacokinetics Study of CJM112 in Hi… NCT04389645 Completed Interferon Gamma Induced Protein 10 (IP-10) in a Clinical De… NCT01017367 Completed Study of MDX-1100 (Anti-CXCL10 Human Monoclonal Antibody) in… NCT00656890 Completed A Study of MDX-1100 in Subjects With Active Ulcerative Colit… NCT01294410 Completed Induction and Maintenance Study of BMS-936557 Patients With … NCT01466374 Completed Induction and Maintenance Study of BMS-936557 in Patients Wi… 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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