key: cord-257958-yehnlabq
authors: Barh, Debmalya; Tiwari, Sandeep; Weener, Marianna E.; Azevedo, Vasco; Góes-Neto, Aristóteles; Gromiha, M. Michael; Ghosh, Preetam
title: Multi-omics-based identification of SARS-CoV-2 infection biology and candidate drugs against COVID-19
date: 2020-10-10
journal: Comput Biol Med
DOI: 10.1016/j.compbiomed.2020.104051
sha: 
doc_id: 257958
cord_uid: yehnlabq

SARS-CoV-2 has ushered a global pandemic with no effective drug being available at present. Although several FDA-approved drugs are currently under clinical trials for drug repositioning, there is an on-going global effort for new drug identification. In this paper, using multi-omics (interactome, proteome, transcriptome, and bibliome) data and subsequent integrated analysis, we present the biological events associated with SARS-CoV-2 infection and identify several candidate drugs against this viral disease. We found that: (i) Interactome-based infection pathways differ from the other three omics-based profiles. (ii) Viral process, mRNA splicing, cytokine and interferon signaling, and ubiquitin mediated proteolysis are important pathways in SARS-CoV-2 infection. (iii) SARS-CoV-2 infection also shares pathways with Influenza A, Epstein-Barr virus, HTLV-I, Measles, and Hepatitis virus. (iv) Further, bacterial, parasitic, and protozoan infection pathways such as Tuberculosis, Malaria, and Leishmaniasis are also shared by this virus. (v) A total of 50 candidate drugs including the prophylaxis agents and pathway specific inhibitors are identified against COVID-19. (vi) Betamethasone, Estrogen, Simvastatin, Hydrocortisone, Tositumomab, Cyclosporin A etc. are among the important drugs. (vii) Ozone, Nitric oxide, and photosensitizer drugs are also identified as possible therapeutic candidates. (viii) Curcumin, Retinoic acids, Vitamin D, Arsenic, Copper, and Zinc may be the candidate prophylaxis agents. Nearly 70% of our identified agents are previously suggested to have anti-COVID-19 effects or under clinical trials. Among our identified drugs, the ones that are not yet tested, need validation with caution while an appropriate drug combination from these candidate drugs along with a SARS-CoV-2 specific antiviral agent is needed for effective COVID-19 management.

The first case of COVID-19 caused by SARS-CoV-2 infection was reported between December 7, 2019 to December 12, 2019 from Huanan, Hubei province, China [1] [2] [3] and as of September 28, 2020, the virus has infected 32,730,945 people with 9,91,224 deaths globally [4] . Currently, the USA is the most affected country by the COVID-19 pandemic with an estimated 6,960,152 infections and 2,02,478 deaths, followed by India (5, 992, 532 infected, 94,503 deaths), and Brazil (4,689,613 infected, 1,40,537 deaths) [4] . Although, the "person-to-person transmission" of SARS-CoV-2 was reported on January 24, 2020 [5] and several quarantine and management strategies were adopted in various countries, the infection could still not be controlled and neither the morbidity.

One of the major causes for this uncontrolled number of infection and deaths is the unavailability of SARS-CoV-2 specific vaccines and antiviral drugs. To overcome the crisis and to identify effective anti-SARS-CoV-2 drugs, repurposing of the existing FDA approved antiviral drugs are given high priority [6] . Although, individual host omics such as interactome [7] , proteome [8] , and transcriptome [9, 10] based pathways of SARS-CoV-2 infected host cell or subject have been described and potential drugs targeting such pathways were reported, so far, no integrative omics based approaches have been employed to study the SARS-CoV-2 infected host biology and pathways in order to predict the potential drugs.

In this paper, we have used an integrative omics approach considering the SARS-CoV-2 infected host interactome, proteome, transcriptome, and bibliome datasets and analysed the COVID-19 associated host genetic information to identify common host pathways that are deregulated during SARS-CoV-2 infection and potential drugs targeting those pathways. We have also reported the SARS-CoV-2 infected host biology/ pathways and potential drugs from each omics-based approach separately.

In this work, we analysed five different peer-reviewed published omics data sets to identify the infection biology and candidate drugs against SARS-CoV-2. The overall approach applied in our work is presented in Fig-1 .

J o u r n a l P r e -p r o o f 

We have used five omics data sets in this analysis. The first data set, designated as the Interactome, outlines SARS-CoV-2 interaction with 332 human (HEK293T/17 cell line) proteins as described by Gordon et al., 2020 [7] . The second data set used in this study is the transcriptome (designated as Transcriptome-1) of lung epithelial cells upon viral infection.

We have considered 88 up-regulated genes from this transcriptome profile [9] . The third data set comprise of 1067 up-regulated genes from the peripheral blood of COVID-19 patients (designated as Transcriptome-2) as described by Xiong 

For identification of potential drugs from various gene sets, we used two additional tools Enrichr (https://amp.pharm.mssm.edu/Enrichr/) [13] and WEB-based GEne SeT AnaLysis Toolkit (WebGestalt, www.webgestalt.org) [13] apart from the ToppFun module of ToppGene suite [12] . Enrichr uses DSigDB (a drug signatures database) [14] and DrugMatrix (a Comprehensive Toxicogenomic Database) for gene set analysis based candidate drug enrichment. All default parameters were used in Enrichr and ToppFun. In WebGestalt [15] , the over-representation analysis was performed using human genome as reference set and DrugBank [16] as the functional database. Default parameters for all these tools were used and a p-value <0.05 was considered significant and used to generate the results.

To understand the network-based biological processes, pathways, and protein-drug interactions for each data set and also the combined data set, NetworkAnalyst 3.0 (www.networkanalyst.ca) [17] was used. Since SARS-COV-2 predominantly infects the lung cells, in our network analysis the human species was used, and to generate the lung tissuespecific Protein-Protein Interaction (PPI) network, from the tissue-specific PPI module of NetworkAnalyst, the lung tissue type was selected. For generic PPI, the IMEx Interactome database (InnateDB) [18] was used. The top ten genes, based on their degree and J o u r n a l P r e -p r o o f Betweenness, were considered. For network-based pathways, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database [19] and for Biological Processes, the PANTHER:BP [20] modules that were integrated with NetworkAnalyst was used. The common pathways and BPs under top ten hits were selected for further analysis. The genes associated with the selected common BPs and Pathways were collected and analysed using ToppFun [12] to identify drugs for these gene sets. Additionally, the Protein-Drug Interactions module of NetworkAnalyst 3.0 [17] was also used to identify drugs for each omics sample-based network using the DrugBank database [16] and filtered with minimum-network.

In this approach, we combined the top ten pathways from each of our analysis (individual and combined omics analysis). Based on their cumulative number of appearances, the common pathways were ranked. Pathways enriched with at least 3 omics-based analyses are presented in the results. We followed a similar approach for selecting BPs also. To identify the most frequent drugs enriched across all our analysis, we also adopted a similar strategy.

Additionally, in this case, we classified all the drugs following the drug categories as suggested by the Drug Information Portal of the U.S. National Library of Medicine (https://druginfo.nlm.nih.gov/drugportal/) and listed the most common drug categories across all the analysis. Further, we also presented the most frequent drugs under each category for better identification of the important drugs. This drug based enrichment was performed for both omics-based and pathway-based drugs that were identified in our analysis.

In our analysis, several common and unique biological processes and drugs are enriched depending on the omic data sets or the analysis tools used. Here, we report the important pathways, biological process, and drugs. The detailed outcomes of each analysis can be found in the supplementary materials.

First, we used the ToppGene suite [12] for candidate gene prioritization. As the bibliome based gene set is a combination of all kinds of SARS-CoV-2 infection associated human genetic data, we used the bibliome based gene set collected through DisGeNET [11] as the training set for this ToppGene based analysis. (Table S1 ).

However, while we combined the top 10 genes from all the candidate gene-based analysis and Table S1) . Gordon et al., 2020 [7] in their PPI study showed that 40% of the interactome are related to endomembrane and ER/Golgi/ mitochondrial trafficking. SARS-CoV-2 predominantly interacts with innate immune pathways, host translation machinery, and Cullin ubiquitin ligase complex. In our interactome set enrichment, we also observed that, the interactome is mostly associated with organelle membranes and involved in intracellular protein targeting or transport. Additionally, we observed that the SARS-CoV-2 interacting human proteins are mostly involved in cell cycle, nuclear pore complex (NPC) disassembly, mitochondrial protein import, and regulation of glucokinase (Table S2 (I)). In our lung-specific interactome analysis, this interactome was also found to be involved in viral carcinogenesis, mRNA splicing, negative regulation of apoptosis, ubiquitin mediated proteolysis, protein processing in endoplasmic reticulum, and spliceosome pathways (Table S3 (I)) .

In their analysis, Gordon et al., 2020 [7] suggested that protein biogenesis inhibitors, Sigma1

and Sigma2 receptor inhibitors, eIF4A inhibitors, Sec61 inhibitors, anti-cancer compounds, and antipsychotic antihistamines could be potential drugs against SARS-CoV-2. In our analysis, we also observed enrichment of anticancer or antipsychotic drugs. Our identified potential drugs are Antineoplastic antibiotics (Idarubicin, Romidepsin, Daunorubicin, Epirubicin), antineoplastic agent (Irinotecan), anti-depressive and anti-psychotic agents (Fluoxetine, Fluphenazine), Estrogens (Coumestrol, conjugated estrogen), anti-bacterial agents (Tunicamycin, Latamoxef), enzyme inhibitor (Thapsigargin), central nervous system agent (Chlorzoxazone), dermatologic agent (Verteporfin), adrenergic agent (Dobutamine), and metal/growth substance (Polaprezinc). Apart from these, Flavin adenine dinucleotide, Guanosine-5'-Diphosphate, Myristic acid, and Kappadione are also enriched in our analysis (Table S2 (I), Table S3 (I)). anticoagulants (Citric acid) are also found to be good candidates (Table S2 (P), Table S3 (P)).

Blanco-Melo et al., 2020 [9] in their in vitro transcriptome (Transcriptome-1) study using normal human bronchial epithelial (NHBE) cells have shown that SARS-CoV-2 induces a low IFN-I and -III and high chemokine signalling. This unique and inflammatory response was not observed in SARS-CoV-1, MERS-CoV, IAV, and RSV [9] . In our analysis, we also found that this up-regulated transcriptome is associated with interferon and cytokine signaling pathways. Further, the Transcriptome-1 is also enriched for Influenza A, Herpes, and Hepatitis C infections (Table S2 (T-1)). The network-based analysis enriched negative regulation of apoptotic process, mRNA splicing, viral carcinogenesis, Hepatitis B, Epstein-Barr virus infection, NOD-like receptor signaling pathway, ubiquitin mediated proteolysis, IL-17 signaling pathway, Measles, Hepatitis C, and Influenza A (Table S3 (T-1)). The results are mostly common to the cellular proteome-based analysis, except the ubiquitin mediated proteolysis, which is not found in case of the proteome data set (Table S3 (P)).

For the up-regulated cellular transcriptome (Transcriptome-1), we identified several potential drugs. These drugs belongs to several drug categories such as-adrenal cortex hormones (Table S2 (T-1), Table S3 (T-1)) Xiong et al., 2020 [10] reported that, upon infection with SARS-COV-2, the patient's blood transcriptome (Transcriptome-2) profile shows increased complement activation, humoral immune response, immunoglobulin mediated response, acute inflammatory response, and lymphocyte apoptosis. We also observed a similar profile for Transcriptome-2, based on our gene set enrichment analysis. However, in addition to these biological processes and pathways, we found that the Malaria pathway is also shared by SARS-CoV-2 (Table S2 (T-2) ). In the network-based lung-specific PPI analysis, we found a profile that is similar to the bronchial epithelial cell specific transcriptome-based (Transcriptome-1) findings by Blanco-Melo et al., 2020 [9] . We found viral carcinogenesis, negative regulation of apoptotic process, endocytosis, mRNA splicing, Epstein-Barr virus infection, Hepatitis B, HTLV-I infection,

Measles, and ubiquitin mediated proteolysis pathways in our analysis (Table S3 (T-2)).

The candidate drugs for this up-regulated patient's blood transcriptome are identified as: antihypertensive agent (Hydrochlorothiazide), antirheumatic agent (Leflunomide), antiasthmatic agent (Theophylline), and anesthetic (Procaine). We also found that anthelmintic drug Lucanthone is enriched in our analysis (Table S2 (T-2), Table S3 (T-2)).

The bibliome-based gene set analysis showed mostly similar biological events that we had (Table S2 (B), Table S3 (B)).

Our combined omics associated gene set enrichment analysis (proteome and transcriptomes) revealed a similar biology and pathways of SARS-CoV-2 as we found in each individual transcriptome analysis. The key BPs and pathways involved are complement activation, humoral immune response, and cytokine and interferon signaling ( (Table S1 (P+T), Table S3 (P+T)).

For the combination of all the five omics data sets, we identified antineoplastic agents (Table S1 (P+T+I+B), Table S3 (P+T+I+B)).

In our analysis, we observed SARS-CoV-2 infection shares other viral pathways such as To identify pathway specific drugs, we used the genes involved in the five most important common pathways (viral processes including all the individual virus pathways, mRNA splicing, ubiquitin mediated proteolysis, cytokine signaling in immune system, and protein processing in endoplasmic reticulum). For each pathway, genes from all the five omics data sets (identified from our network based analysis and ToppFun) were combined and ToppFun [12] , WebGestalt [15] , and Enrichr [13] were used to identify gene set specific drugs. (Table S4) .

Additionally, several candidate drugs are also identified for each pathway. Glibenclamide (Table S4) .

Since we identified several pathways, biological process, and drugs in our various analyses, to identify the most important ones, we combined all the results and then ranked them according to their number of appearances. We selected the pathways, biological process, and drugs that are commonly enriched in at least 3 of our omics-based analysis.

While we combined biological processes from all our analysis and performed the ranking, we found that RNA splicing, viral process, mRNA processing, mRNA splicing via spliceosome, negative regulation of apoptotic process, regulation of cell cycle, rhythmic process, cell proliferation, defense response, immune system process, protein phosphorylation, and complement activation are the top 15 pathways involved in the SARS-CoV-2 infection process ( Fig-2A , Table S5 ). Similarly, Epstein-Barr virus infection, HTLV-I infection, pathways in cancer, cell cycle, cytokine signaling in immune system, focal adhesion, Hepatitis B, Influenza A, Leishmaniasis, ubiquitin mediated proteolysis, viral carcinogenesis, and mRNA splicing/spliceosome are found as top pathways (Fig-2B , Table S5 ). Apart from these pathways, Measles, Tuberculosis, Toxoplasmosis, and Malaria pathways are also found to be common in at least three of our analyses (Fig-2B , Table S5 ). (Fig-4) . Purvalanol, Resveratrol, Sorafenib, Tanespimycin, and Vorinostat (Fig-5A , Table S7 ). The identified top drug categories are antineoplastic agents, analgesics, anti-infective agents, antibacterial agents, enzyme inhibitors, metal/ growth substances, alkylating agents, antihemophilic factors, and Vitamin D that have at least 3 drugs in each category (Fig-5B , (Fig-6) . 

Among the anticancer drugs identified in our analysis, a combination of topoisomerase inhibitors (Irinotecan and Etoposide) is reported to be an effective treatment strategy to counter cytokine storms in critically ill COVID-19 patients [21] . Our identified Doxorubicin was previously suggested for repurposing to treat COVID-19 patients [22] . Another identified anticancer drug Dasatinib is found to be safer to treat Chronic Myeloid Leukemia (CML) patients infected with SARS-CoV-2 [23] . Binimetinib, Brigatinib , Seliciclib, Sorafenib, and

Vorinostat were also previously predicted to be effective against SARS-CoV-2 infection [24] [25] [26] [27] . Therefore, the additional anticancer drugs identified by our analyses, such as Phenethyl isothiocyanate, Abciximab, Lucanthone, Cisplatin, Tositumomab, Procarbazine, and Noscapine may also be tested against SARS-CoV-2.

Our identified antidepressant drug Fluoxetine (Prozac) was previously reported to inhibit the replication of SARS-CoV-2 [29] and therefore, may be tested for potential COVID-19

therapy. The antipsychotic medicine Fluphenazine is also enriched in our analysis that has previously been tested on SARS-CoV-2 [30] . Similarly, Sertraline (a Serotonin (5-HT) inhibitor), that is identified in our study, has recently been found to block SARS CoV 2 endocytosis and suggested for drug repurposing against COVID-19 [31] . Thus, the additional J o u r n a l P r e -p r o o f antidepressant/ antipsychotic drugs identified by our analyses, such as Droperidol (antidopaminergic), may also be tested to understand their effectiveness against SARS-CoV-2.

In our analysis, several Cyclooxygenase (COX) inhibitors and anti-histamine compounds found potential against COVID-19. Among these drugs, Indomethacin (COX inhibitor) is

shown to exert its anti-SARS-COV-2 activity in canine coronavirus model [32] . Further, Indomethacin in combination with Resveratrol (also identified in our analysis) has been proposed to be used for treating COVID 19 [33] . Two other COX inhibitors (Loxoprofen and Acetaminophen) identified in our analysis were also previously tested in silico for their potential antiviral activity against SARS-CoV-2 [34] . Niflumic acid which is also a COX inhibitor as well as a Ca2+-activated Clchannel blocker is also enriched in our analysis and also been previously identified as a potential drug against SARS-CoV-2 [35] . Other antiinflammatory drugs such as Andrographolide, Apremilast (phosphodiesterase type 4 inhibitor) that are identified in our analysis were also predicted by previous studies as potential COVID-19 therapeutics [36, 37] . In our analysis, we also found the rheumatoid arthritis drug Tofacitinib as a good candidate for COVID-19 management. Tofacitinib is a JAK inhibitor and reduces immune system inflammation and is currently under clinical trials for COVID-19 treatment (NCT04415151, NCT04412252), Therefore, the additional anti-allergic and antiinflammatory drugs identified by our analyses including Sulindac (COX inhibitor) and

Terfenadine (H1-receptor binding anti-histamine drug) need attention to be tested against SARS-CoV-2. Similarly, other channel inhibitors enriched in our analysis such as Acetohexamide (ATP-dependent K + channel inhibitor), Suloctidil (Calcium antagonist), Glibenclamide (ATP-sensitive potassium channels inhibitor), and Thapsigargin (a sarco/endoplasmic reticulum Ca²⁺ ATPase inhibitor) may also be tested.

Tissue plasminogen activators (TPA), antihemophilic factors, immune globulin, and antithymocyte globulin are found to be good candidates in COVID-19 treatment as per our various omics-based analyses. Reports suggest that, TPA with targeted anti-inflammatory treatment may be a potential therapy against COVID-19 [38] . Tenecteplase, a TPA, that is identified in our analysis, is considered in managing acute coronary syndromes associated with COVID-19 [39] and is currently under clinical trial to manage COVID-19 patients (NCT04505592). Lanoteplase, a third generation recombinant plasminogen derived from Alteplase, is also identified in our analysis. Alteplase is currently under clinical trial to J o u r n a l P r e -p r o o f evaluate its efficacy against COVID-19 (NCT04357730). We also found Antihemophilic factors could be also effective against COVID-19. The Factor VIII which is an Antihemophilic factor is elevated in COVID-19 patients [40] . Therefore, Factor VIII inhibitors may be a potential therapeutic strategy. Immune globulin is also enriched in our analysis. Immune globulin is present in plasma and convalescent plasma therapy is effective in treating COVID-19 patients [41] . Our identified human serum albumin may be a good delivery vehicle to maximize the cellular internalization and enhancement of other drugs used in COVID-19 treatment [42] . Since most of our identified blood based components are suggested to be effective in COVID-19, the Anti-thymocyte globulin which is also identified in our analysis may also be tested for its efficacy in the management of SARS-CoV-2

infection.

Estrogen or Estrogen analogues are enriched in almost all of our omics data set-based analyses. Dimorphism of COVID-19 infection has been recently reported. Men are found to be more prone to SARS-CoV-2 infection or COVID-19 associated deaths as compared to women [43] . The disease severity of COVID-19 is also found to be dependent on ERα:ERβ expression ratio and E2 level [43] . Reports also suggest that the expression of human ACE2, which is the receptor for SARS-CoV-2, is regulated by Estrogen [44] . Therefore, Estradiol agonist may have a protective role against COVID-19 [45] . Recently, Estrogen patch is under clinical trial to evaluate its efficacy against COVID-19 (NCT04359329). In our analysis, we observed that Phytoestrogens including Coumestrol could also be a potential therapeutic against COVID-19.

We observed that, steroids could play an important role in fighting against COVID-19. The corticosteroid Dexamethasone and Methylprednisolone which we identified in our analysis, were previously found to significantly reduce mortality rates from COVID-19 [46, 47] and currently under clinical trials (NCT04327401, NCT04323592). The other corticosteroid that is predominantly enriched in our integrative omics approach is Betamethasone. Betamethasone is found to be safe for pregnant subjects infected with SARS-CoV-2 [48] and is currently also under clinical trial at sites where Dexamethasone is not easily available (NCT04509973).

Therefore, other corticosteroids identified in our analysis such as Fludrocortisone acetate may also be tested against COVID-19. Among our identified glucocorticoids, Hydrocortisone has been tested on COVID-19 patients [49] and Prednisone and Procaine may be tested in the coming days.

J o u r n a l P r e -p r o o f

No known targeted antiviral drug is enriched in our analysis. However, we identified several antibiotics. Among these antibiotics, Clindamycin was previously suggested by a computational approach [50] and is recommended to treat SARS-CoV-2 infection [51] . We identified two additional antitumor antibiotics, Geldanamycin and Tanespimycin, which are also heat shock protein 90 (HSP90) inhibitors. While Geldanamycin is suggested for COVID-19 treatment [52] , Tanespimycin was previously identified by an in silico method [52] . 

Apart from sharing various viral pathways, we also found that SARS-CoV-2 shares pathways associated with Tuberculosis, Leishmaniasis, and Malaria. The antimalarial drug

Hydroxychloroquine alone or in combination with Remdesivir effectively inhibits SARS-CoV-2 infection [54, 55] . Hydroxychloroquine is under clinical trial (NCT04345692). In our analysis, we found that Artenimol or Artesunate, an alternative of Chloroquine could also be effective in treating COVID-19. Moreover, Artesunate was previously predicted to be a good candidate against SARS-CoV-2 [56, 57] and is currently under clinical trial (NCT04387240).

In our analysis, we found immunosuppressant drugs may also be effective against COVID-19.

Among the identified immunosuppressants, Cyclosporin A is enriched in our multiple analyses. A recent in vitro study indicates that Cyclosporin A is effective against SARS-CoV-2 [58] and therefore, can be a potential drug to be further tested in COVID-19 patients [59] .

Cyclosporin A is currently under clinical trials (NCT04412785, NCT04451239) . Similarly, the other immunosuppressant Leflunomide identified in our analyses is also under clinical trial (NCT04361214).

In our integrative omics approach, we found that Ozone could be a potential therapy against

Ozone-based management for early control of COVID-19 are under various stages of clinical trials (NCT04366089, NCT04370223). Nitric oxide, which is known to provide innate antiviral protection [61] , is also enriched in our analysis. Nitric oxide inhalation is recently reported to be beneficial to manage the acute respiratory distress syndrome due to SARS-CoV-2 infection [62] and currently Nitric oxide inhalation therapy is under clinical trials to understand its efficacy in managing COVID-19 patients (NCT04383002, NCT04421508, NCT04306393). Verteporfin, a photosensitizer drug for photodynamic therapy is found to be an effective drug in our analysis. Verteporfin is also previously reported to be a potential antiviral therapy against SARS-CoV-2 [63] .

In our multi-omics-based analysis, Acetylcysteine is enriched. Acetylcysteine is a mucolytic agent that can prevent the severity of SARS- ). Therefore, our results suggest that our analytic approach in this study is highly accurate and Curcumin, Retinoic Acids, and Ergocalciferol could be good prophylaxis candidates against COVID-19.

Arsenenous acid and Arsenic trioxide are identified both in our candidate gene-based integrative omics analysis as well as viral pathway-based analysis. Recent in silico analysis suggests that Arsenic based drug Darinaparsin may inhibit SARS-CoV-2 RNA polymerase and Proteases, and therefore, may inhibit viral replication [72] . In homeopathy medicine Arsenicum album 30, prepared from Arsenic trioxide, is recommended as a prophylactic medicine against SARS-CoV-2 infection [73] . In our analysis, Copper is found to inhibit all three important pathways: mRNA splicing, Ubiquitin mediated proteolysis, and protein processing in endoplasmic reticulum pathways. Copper irreversibly disintegrates Coronavirus genomes, envelope, and spike [74] . Report also suggests that enrichment of copper levels in J o u r n a l P r e -p r o o f plasma could boost both the innate and adaptive immunity [75] and therefore, Copper could also be a good prophylactic agent against SARS-CoV-2 infection. Similarly, Polaprezinc is identified as a potential molecule to block protein processing in the endoplasmic reticulum pathway. Zinc supplementation is recommended as a good prophylaxis and therapeutic strategy against COVID-19 [76] . Currently, several clinical trials are on-going to evaluate the anti-COVID-19 efficacy of Zinc in combination with other drugs (NCT04351490, NCT04447534).

In this work, we have used four different host specific omics data sets that were recently published along with a bibliome based gene set to identify the SARS-CoV-2 infection biology, potential drugs, and prophylaxis agents against this virus. Based on our individual omics-based or their combination-based analysis, it is evident that the SARS-CoV-2 infection shares various virus, bacteria, and protozoon infection pathways. Although, we identified several candidate drugs and prophylaxis candidates, we were not able to identify any SARS-CoV-2 specific antiviral agent. Nearly ~70% of our identified agents were previously reported to have anti-COVID-19 activity, and a number of these agents are currently under various stages of clinical trials. Since the most observed effective drugs/agents are among those that were used (or introduced) previously, our used integrative omics-based methodology is highly credible and warrants its wide-spread adoption and application. This method would also be highly applicable for drug repositioning research in future waves of COVID-19 infection and also other possible pandemics. However, as SARS-CoV-2 shares multiple pathogens' infection pathways, individual drugs targeting a single pathway may not be effective and therefore, a combination of drugs needs to be formulated to block the multiple infection pathways of this virus. Further, the prophylaxis agents identified here also need an effective combination. All these identified drugs need multiple validations, large scale clinical trials, and caution before their use in COVID-19 management.

DB: conceived and designed the experiment, data collection and analysis, result interpretation, and wrote the paper; ST: preformed re-analysis; PG: data interpretation and edited the article, MEI, AGN, MMG and VA: provided technical inputs.

Authors declare no competing interest.

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Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Artesunate: could be an alternative drug to chloroquine in COVID-19 treatment?

In-silico Studies of Antimalarial-agent Artemisinin and Derivatives Portray More Potent Binding to Lys353 and Lys31-Binding Hotspots of SARS-CoV-2 Spike Protein than Hydroxychloroquine: Potential Repurposing of Artenimol for COVID-19, chemrxiv

Drug repurposing screens reveal FDA approved drugs active against SARS-Cov-2, bioRxiv

Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

Potential Cytoprotective Activity of Ozone Therapy in SARS-CoV-2/COVID-19

The nitric oxide pathway provides innate antiviral protection in conjunction with the type I interferon pathway in fibroblasts

Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome

Potent antiviral effect of protoporphyrin IX and verteporfin on SARS-CoV-2 infection, bioRxiv

Catechin and Curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: insights from Computational study and implication for intervention

A Novel Combination of Vitamin C, Curcumin and Glycyrrhizic Acid Potentially Regulates Immune and Inflammatory Response Associated with Coronavirus Infections: A Perspective from System Biology Analysis

Inhibitory Effects of Resveratrol on the Epstein-Barr Virus Lytic Cycle

Resveratrol as a Novel Anti-Herpes Simplex Virus Nutraceutical Agent: An Overview

Effective inhibition of MERS-CoV infection by resveratrol

Natural compounds as potential inhibitors of novel coronavirus (COVID-19) main protease: An in silico study

Vitamin D deficiency and co-morbidities in COVID-19 patients -A fatal relationship?

Letter: Covid-19, and vitamin D

In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA dependent RNA polymerase (RdRp) and Necessary Proteases

Advisory for Corona virus Homoeopathy for Prevention of Corona virus Infections Unani Medicines useful in symptomatic management of Corona Virus infection

Is copper beneficial for COVID-19 patients?

Potential role of zinc supplementation in prophylaxis and treatment of COVID-19

HTLV-I, Measles, and Hepatitis virus infection pathways. • SARS-CoV-2 also shares Tuberculosis, Malaria, and Leishmaniasis infection pathways. • mRNA splicing, cytokine and IFN signaling, and ubiquitin are important pathways. • Anticancer, antipsychotic, anti-inflammatory, antibiotic, immunosuppressant, corticosteroid

Cyclosporin A are top candidate drugs

Nitric oxide, and photosensitizer drugs are also important against COVID-19

Retinoic acids, Vit-D, Arsenic, Copper, and Zinc are candidate prophylaxis agents

• ~70% of our identified drugs are previously suggested or under clinical trial for COVID-19. • Our newly identified candidate drugs need validation with caution

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