Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium

Authors

Rajaneesh K. Gupta, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Enyinna L. Nwachuku, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Benjamin E. Zusman, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Ruchira M. Jha, Departments of Neurology, Neurobiology, Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, United States of America.Follow
Ava M. Puccio, Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

Document Type

Article

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.

Medical Subject Headings

Antiviral Agents (therapeutic use); Drug Evaluation, Preclinical (methods); Drug Repositioning (methods); Epithelial Cells (drug effects); Epithelium (drug effects); Humans; Respiratory Mucosa (drug effects, metabolism, virology); Respiratory System (drug effects); SARS-CoV-2 (drug effects, genetics, pathogenicity); COVID-19 Drug Treatment

Publication Date

1-1-2021

Publication Title

PloS one

E-ISSN

1932-6203

Volume

16

Issue

9

First Page

e0257784

PubMed ID

34582497

Digital Object Identifier (DOI)

10.1371/journal.pone.0257784

Recommended Citation

Gupta, Rajaneesh K.; Nwachuku, Enyinna L.; Zusman, Benjamin E.; Jha, Ruchira M.; and Puccio, Ava M., "Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium" (2021). Neurology. 1335.
https://scholar.barrowneuro.org/neurology/1335