Host transcriptome-guided drug repurposing for COVID-19 treatment: a meta-analysis based approach

Abstract

Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a pandemic by the World Health Organization, and the identification of effective therapeutic strategy is a need of the hour to combat SARS-CoV-2 infection. In this scenario, the drug repurposing approach is widely used for the rapid identification of potential drugs against SARS-CoV-2, considering viral and host factors. Methods We adopted a host transcriptome-based drug repurposing strategy utilizing the publicly available high throughput gene expression data on SARS-CoV-2 and other respiratory infection viruses. Based on the consistency in expression status of host factors in different cell types and previous evidence reported in the literature, pro-viral factors of SARS-CoV-2 identified and subject to drug repurposing analysis based on DrugBank and Connectivity Map (CMap) using the web tool, CLUE. Results The upregulated pro-viral factors such as TYMP, PTGS2, C1S, CFB, IFI44, XAF1, CXCL2, and CXCL3 were identified in early infection models of SARS-CoV-2. By further analysis of the drug-perturbed expression profiles in the connectivity map, 27 drugs that can reverse the expression of pro-viral factors were identified, and importantly, twelve of them reported to have anti-viral activity. The direct inhibition of the PTGS2 gene product can be considered as another therapeutic strategy for SARS-CoV-2 infection and could suggest six approved PTGS2 inhibitor drugs for the treatment of COVID-19. The computational study could propose candidate repurposable drugs against COVID-19, and further experimental studies are required for validation.

Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

“…In comparison with other studies which employed similar computational approach for drug repurposing based on transcriptome reversal [ 27 , 28 , 29 , 31 ], we observed only a minor or no overlap of the drug candidate lists. Shared candidates were ADRA1B antagonists (nortriptyline in our study), as well as ACE inhibitor perindopril and NR1I2 agonists (econazole and ritonavir in our study) that were also identified by El-Hachem et al [ 30 ].…”

“…Several in silico drug repurposing studies based on a transcriptome reversal approach have already been published in the context of COVID-19 [ 27 , 28 , 29 , 30 , 31 ]. However, one common issue in such studies is a complete lack or insufficiency of the criteria for inclusion of datasets in the analysis which may then produce misleading results.…”

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach

“…However, the scale and cost of this global health crisis is such that effective drug therapies have an important and complementary role to play in treating this disease. In recent months, in silico studies have identified putative repurposable drugs for treating COVID-19 20 , 50 , 74 – 77 . Many of these studies exploit the finding that SARS-CoV-2 may enter the cell by binding to angiotensin converting enzyme 2 (ACE2) 78 and utilize a combination of structural and biomedical data to identify drug candidates 20 .…”

A computational framework of host-based drug repositioning for broad-spectrum antivirals against RNA viruses

“…Compared to virus-centered antiviral strategy that targets viral genes to directly interfere with virus reproduction and infection, a host-centered antiviral approach has several advantages such as (1) functional host genes are more conserved and evolutionally stable than viral genes, which makes host-targeting drugs more tolerant to frequent viral mutations than those virus-targeting counterparts; 2) different viruses may share a similar set of host genes during certain stages of viral life cycle, which underlines the basis of developing broad-spectrum antivirals so that one host-targeting drug may treat multiple virus infection; and (3) there are significantly more targeted drugs approved for host genes than those for viral genes, thus likely increasing the success rate of drug repurposing by adopting host-centered strategy. Previous studies have extensively tried targeting host genes for developing antiviral solutions ( Ackerman et al., 2018 ; Bosl et al., 2019 ; Li et al., 2019 ; Loganathan et al., 2020 ; Luo et al., 2017 ; Saiz et al., 2018 ; Zhou et al., 2020 ). Host receptors mediating viral entrance into the cells represent the most popular host targets for drugs to block viral infection.…”