In silico Drug Repurposing to combat COVID-19 based on Pharmacogenomics of Patient Transcriptomic Data

Das, Shaoli; Camphausen, Kevin; Shankavaram, Uma

doi:10.21203/rs.3.rs-39128/v1

Cited by 4 publications

(3 citation statements)

References 30 publications

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“…It has been identified as a candidate for downregulating the androgen biosynthesis pathway, which is upregulated due to COVID-19, as well as for downregulating the macrophages, monocytes and dendritic cells pathway potentially linked to severe symptoms in COVID-19 patients [ 93 ]. Das et al [ 93 ] proposed the drugs vorinostat, panobinostat, azacitidine, and clofarabine, all identified here as candidates to treat multiorgan damage produced by COVID-19, for downregulating the mitotic cell cycle-related pathways and proteasome activity, which play an important role in coronaviral replication. Azacitidine and vorinostat are proposed as drugs to upregulate the CTL or Interleukin 2 pathways, which are important for antiviral immune responses [ 93 ].…”

Section: Discussionmentioning

confidence: 99%

“…Das et al [ 93 ] proposed the drugs vorinostat, panobinostat, azacitidine, and clofarabine, all identified here as candidates to treat multiorgan damage produced by COVID-19, for downregulating the mitotic cell cycle-related pathways and proteasome activity, which play an important role in coronaviral replication. Azacitidine and vorinostat are proposed as drugs to upregulate the CTL or Interleukin 2 pathways, which are important for antiviral immune responses [ 93 ]. Azacitidine was indeed identified by Gordon et al [ 45 ] as possible treatment options for COVID-19.…”

Section: Discussionmentioning

confidence: 99%

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Protein-Driven Mechanism of Multiorgan Damage in COVID-19

Estrada¹

2020

Medicine in Drug Discovery

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We propose a new plausible mechanism by mean of which SARS-CoV-2 produces extrapulmonary damages in severe COVID-19 patients. The mechanism consist on the existence of vulnerable proteins (VPs), which are (i) mainly expressed outside the lungs; (ii) their perturbations is known to produce human diseases; and (iii) can be perturbed directly or indirectly by SARS-CoV-2 proteins. These VPs are perturbed by other proteins, which are: (i) mainly expressed in the lungs, (ii) are targeted directly by SARS-CoV-2 proteins, (iii) can navigate outside the lungs as cargo of extracellular vesicles (EVs); and (iv) can activate VPs via subdiffusive processes inside the target organ. Using bioinformatic tools and mathematical modeling we identifies 26 VPs and their 38 perturbators, which predict extracellular damages in the immunologic endocrine, cardiovascular, circulatory, lymphatic, musculoskeletal, neurologic, dermatologic, hepatic, gastrointestinal, and metabolic systems, as well as in the eyes. The identification of these VPs and their perturbators allow us to identify 27 existing drugs which are candidates to be repurposed for treating extrapulmonary damage in severe COVID-19 patients. After removal of drugs having undesirable drug-drug interactions we select 7 drugs and one natural product: apabetalone, romidepsin, silmitasertib, ozanezumab, procaine, azacitidine, amlexanox, volociximab, and ellagic acid, whose combinations can palliate the organs and systems found to be damaged by COVID-19. We found that at least 4 drugs are needed to treat all the multiorgan damages, for instance: the combination of romidepsin, silmitasertib, apabetalone and azacitidine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Protein-Driven Mechanism of Multiorgan Damage in COVID-19

Estrada¹

2020

Medicine in Drug Discovery

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“…For example, Pahm et al established a deep learning model based on the Broad Institute Connectivity Map (CMAP) dataset, and applied the model for patient-specific drug repurposing for COVID-19 4 . Das et al also carried out a screening of potential drugs by comparing CMAP dataset and transcriptome data of SARS-CoV-2 infected patients 5 . If a drug’s targeted host receptors interact with SARS-CoV-2, this drug could be a potential candidate for the infection.…”

Section: Introductionmentioning

confidence: 99%

Integrative web-based analysis of omics data for study of drugs against SARS-CoV-2

Wang

Huang

et al. 2021

Sci Rep

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Research on drugs against SARS-CoV-2 (cause of COVID-19) has been one of the major world concerns at present. There have been abundant research data and findings in this field. The interference of drugs on gene expression in cell lines, drug-target, protein-virus receptor networks, and immune cell infiltration of the host may provide useful information for anti-SARS-CoV-2 drug research. To simplify the complex bioinformatics analysis and facilitate the evaluation of the latest research data, we developed OmiczViz (http://medcode.link/omicsviz), a web tool that has integrated drug-cell line interference data, virus-host protein–protein interactions, and drug-target interactions. To demonstrate the usages of OmiczViz, we analyzed the gene expression data from cell lines treated with chloroquine and ruxolitinib, the drug-target protein networks of 48 anti-coronavirus drugs and drugs bound with ACE2, and the profiles of immune cell infiltration between different COVID-19 patient groups. Our research shows that chloroquine had a regulatory role of the immune response in renal cell line but not in lung cell line. The anti-coronavirus drug-target network analysis suggested that antihistamine of promethaziney and dietary supplement of Zinc might be beneficial when used jointly with antiviral drugs. The immune infiltration analysis indicated that both the COVID-19 patients admitted to the ICU and the elderly with infection showed immune exhaustion status, yet with different molecular mechanisms. The interactive graphic interface of OmiczViz also makes it easier to analyze newly discovered and user-uploaded data, leading to an in-depth understanding of existing findings and an expansion of existing knowledge of SARS-CoV-2. Collectively, OmicsViz is web program that promotes the research on medical agents against SARS-CoV-2 and supports the evaluation of the latest research findings.

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SARS-COV-2 as potential microRNA sponge in COVID-19 patients

Wang

et al. 2022

BMC Med Genomics

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Background MicroRNAs (miRNAs) are a class of small non-coding RNA that can downregulate their targets by selectively binding to the 3′ untranslated region (3′UTR) of most messenger RNAs (mRNAs) in the human genome. MiRNAs can interact with other molecules such as viruses and act as a mediator for viral infection. In this study, we examined whether, and to what extent, the SARS-CoV-2 virus can serve as a “sponge” for human miRNAs. Results We identified multiple potential miRNA/target pairs that may be disrupted during SARS-CoV-2 infection. Using miRNA expression profiles and RNA-seq from published studies, we further identified a highly confident list of 5 miRNA/target pairs that could be disrupted by the virus’s miRNA sponge effect, namely hsa-miR-374a-5p/APOL6, hsa-let-7f-1-3p/EIF4A2, hsa-miR-374a-3p/PARP11, hsa-miR-548d-3p/PSMA2 and hsa-miR-23b-3p/ZNFX1 pairs. Using single-cell RNA-sequencing based data, we identified two important miRNAs, hsa-miR-302c-5p and hsa-miR-16-5p, to be potential virus targeting miRNAs across multiple cell types from bronchoalveolar lavage fluid samples. We further validated some of our findings using miRNA and gene enrichment analyses and the results confirmed with findings from previous studies that some of these identified miRNA/target pairs are involved in ACE2 receptor network, regulating pro-inflammatory cytokines and in immune cell maturation and differentiation. Conclusion Using publicly available databases and patient-related expression data, we found that acting as a “miRNA sponge” could be one explanation for SARS-CoV-2-mediated pathophysiological changes. This study provides a novel way of utilizing SARS-CoV-2 related data, with bioinformatics approaches, to help us better understand the etiology of the disease and its differential manifestation across individuals.

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In silico Drug Repurposing to combat COVID-19 based on Pharmacogenomics of Patient Transcriptomic Data

Cited by 4 publications

References 30 publications

Protein-Driven Mechanism of Multiorgan Damage in COVID-19

Protein-Driven Mechanism of Multiorgan Damage in COVID-19

Integrative web-based analysis of omics data for study of drugs against SARS-CoV-2

SARS-COV-2 as potential microRNA sponge in COVID-19 patients

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