Integrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal

El-Hachem, Nehmé; Eid, Edward; Nemer, Georges; Dbaibo, Ghassan; Abbas, Ossama; Rubeiz, Nelly; Zeineldine, Salah; Matar, Ghassan M.; Bikorimana, Jean-Pierre; Shammaa, Riam; Haibe‐Kains, Benjamin; Kurban, Mazen; Rafei, Moutih

doi:10.1016/j.isci.2020.101697

Cited by 15 publications

(10 citation statements)

References 53 publications

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“…S2 D). As expected, immune related pathways like interleukin signaling have also been reported by others following analysis of SARS-CoV-2 infection datasets 18 , 19 . Our workflow (modified) has also provided in silico confirmation of the anti-inflammatory and pro-immune effects of oxytocin 70 and the antidepressant fluoxetine 71 , which is also currently in trial for the treatment of COVID-19 (NCT04377308, and others).…”

Section: Resultssupporting

confidence: 83%

“…Such studies identified FDA-approved antivirals 17 and a broad range of kinase inhibitors as potential candidate treatments for COVID-19 18 – 20 . Importantly, transcriptional analyses have provided additional support for the use of drugs like dexamethasone 17 and chlorpromazine 19 that are already undergoing clinical trial. Analyzing the transcriptional changes induced by SARS-CoV-2 infection has also offered significant insight into the genes and biological pathways 17 , 18 , 21 – 23 that are altered in disease, implicating cellular inflammatory responses, particularly interferon pathways, in COVID-19 19 , 24 , 25 .…”

Section: Introductionmentioning

confidence: 99%

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

O’Donovan

Imami

Eby

et al. 2021

Sci Rep

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The COVID-19 pandemic caused by the novel SARS-CoV-2 is more contagious than other coronaviruses and has higher rates of mortality than influenza. Identification of effective therapeutics is a crucial tool to treat those infected with SARS-CoV-2 and limit the spread of this novel disease globally. We deployed a bioinformatics workflow to identify candidate drugs for the treatment of COVID-19. Using an “omics” repository, the Library of Integrated Network-Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID-19 drugs and publicly available SARS-CoV-2 infected cell lines to identify novel therapeutics. We identified a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID-19, the remaining 12 have antiviral properties and 6 have antiviral efficacy against coronaviruses specifically, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug findings are discordant with (i.e., reverse) SARS-CoV-2 transcriptome signatures generated in vitro, and a subset are also identified in transcriptome signatures generated from COVID-19 patient samples, like the MEK inhibitor selumetinib. Overall, our findings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID-19 and identify promising novel targets that are worthy of further investigation.

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Section: Resultssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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

O’Donovan

Imami

Eby

et al. 2021

Sci Rep

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“…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 ]. This limited agreement between similar studies may stem from using different starting transcriptomic datasets as well as from differences in the criteria applied in the dataset and DEGs selection procedure.…”

Section: Discussionsupporting

confidence: 66%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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A year after the initial outbreak, the COVID-19 pandemic caused by SARS-CoV-2 virus remains a serious threat to global health, while current treatment options are insufficient to bring major improvements. The aim of this study is to identify repurposable drug candidates with a potential to reverse transcriptomic alterations in the host cells infected by SARS-CoV-2. We have developed a rational computational pipeline to filter publicly available transcriptomic datasets of SARS-CoV-2-infected biosamples based on their responsiveness to the virus, to generate a list of relevant differentially expressed genes, and to identify drug candidates for repurposing using LINCS connectivity map. Pathway enrichment analysis was performed to place the results into biological context. We identified 37 structurally heterogeneous drug candidates and revealed several biological processes as druggable pathways. These pathways include metabolic and biosynthetic processes, cellular developmental processes, immune response and signaling pathways, with steroid metabolic process being targeted by half of the drug candidates. The pipeline developed in this study integrates biological knowledge with rational study design and can be adapted for future more comprehensive studies. Our findings support further investigations of some drugs currently in clinical trials, such as itraconazole and imatinib, and suggest 31 previously unexplored drugs as treatment options for COVID-19.

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“…This finding has renewed the interest in finding safer and more effective immunomodulatory therapeutics to treat COVID-19. Analysis of lung transcriptome and the circulatory inflammatory cytokines profiles of COVID-19 patients indicated that NF-κB, inflammasome, IL-6 trans-signaling, and HMGB1 signaling may be driving the CRS ( El-Hachem et al, 2020 ; Lee et al, 2020 ). We present several lines of evidence to illustrate how pleiotropic effects of curcumin could dampen CRS and mitigate the progression to ARDS and or sepsis in COVID-19 patients.…”

Section: Immunomodulatory Activity Of Curcumin Suppress Cytokine Relementioning

confidence: 99%

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19

Thimmulappa

Mudnakudu-Nagaraju

Shivamallu

et al. 2021

Heliyon

126

112

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Coronavirus disease-19 (COVID-19), a devastating respiratory illness caused by SARS-associated coronavirus-2 (SARS-CoV-2), has already affected over 64 million people and caused 1.48 million deaths, just 12 months from the first diagnosis. COVID-19 patients develop serious complications, including severe pneumonia, acute respiratory distress syndrome (ARDS), and or multiorgan failure due to exaggerated host immune response following infection. Currently, drugs that were effective against SARS-CoV are being repurposed for SARS-CoV-2. During this public health emergency, food nutraceuticals could be promising prophylactic therapeutics for COVID-19. Curcumin, a bioactive compound in turmeric, exerts diverse pharmacological activities and is widely used in foods and traditional medicines. This review presents several lines of evidence, which suggest curcumin as a promising prophylactic, therapeutic candidate for COVID-19. First, curcumin exerts antiviral activity against many types of enveloped viruses, including SARS-CoV-2, by multiple mechanisms: direct interaction with viral membrane proteins; disruption of the viral envelope; inhibition of viral proteases; induce host antiviral responses. Second, curcumin protects from lethal pneumonia and ARDS via targeting NF-κB, inflammasome, IL-6 trans signal, and HMGB1 pathways. Third, curcumin is safe and well-tolerated in both healthy and diseased human subjects. In conclusion, accumulated evidence indicates that curcumin may be a potential prophylactic therapeutic for COVID-19 in the clinic and public health settings.

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Integrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal

Cited by 15 publications

References 53 publications

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

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

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

Antiviral and immunomodulatory activity of curcumin: A case for prophylactic therapy for COVID-19

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