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Integration and visualization of COVID-19 molecular mechanisms using Pathway Studio

Posted on April 6th, 2020 by in COVID-19

Integrating the rich information from multi-omics data has been a popular approach to drugs discovery and development against novel 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To facilitate the integrative analysis and power the global researchers, we have constructed various models that contain biomedical pathways information for SARS-CoV and SARS-CoV-2. Now they are available for public access.

In my previous blog, I discussed 5 research strategies, including the recent 2 additional directions – evaluating drugs that inhibit endocytosis and drugs that inhibit virus enzymes, e.g., viral proteases and the viral replicase. In this article, I would like to share all the models and pathways mentioned in my previous blog. These models cover the following topics:

  • COVID-19 clinical path
  • COVID-19 protein complexes
  • Repurposable drugs for COVID-19
  • Drugs that should be counter-indicated with COVID-19
  • SARS-CoV molecular biology
  • Mechanisms used by SARS-CoV to inhibit the immune response
  • Host-virus interactions
  • Cytokine storm
  • ACE2 biology

Read below for the details and the links to these biochemical pathways. Feel free to contact me if you would like to discuss these models further. 

COVID19 clinical pathway

COVID19 protein complexes – depicts all SARS-CoV2 proteins and explains their role in viral biology

Drugs repurposed for COVID19

Chloroquine inhibits autophagy. Inhibition of autophagy blocks virus penetration into a cell but also blocks antigen presentation by macrophages, which does not allow them to activate adaptive immunity with T-cells and B-cells.

Coronavirus protein inhibitors. COVID19 specific inhibitors has yet to be developed but existing anti-SARS-CoV inhibitors maybe effective against COVID19 in their absence.

Drugs for SARS-CoV and MERS. 44 drug ant-SARS drug activate autophagy and 12 inhibit autophagy

Drugs re-purposed against COVID19 by Fan et al. 2020 appear to act through activation of autophagy

Drugs regulating Autophagy. 337 drugs are known to activate autophagy, 102 drugs are known to inhibit autophagy.

Host Proteases in COVID19 entry. Better multi-targeted protease inhibitors are needed to inhibit all proteases capable of activating SARS entry into a cell.

Vγ9Vδ2 cells inhibit SARS-CoV. “Human Vγ9Vδ2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. Vγ9Vδ2 T lymphocytes proliferate in response to HIV-infected cells and can exert a powerful cytotoxic activity against HIV-infected targets. S.c. injections of low doses of IL-2 combined with i.v. administration of aminobisphosphonate or PP-ME drugs substantially expand the pool of Vγ9Vδ2 Th1 effectors in vivo.” (Casetti et al 2005)

Drugs may have counter-indication with COVID19

Drugs inducing ACE2 expression

SARS molecular biology

SARS induces Autophagosome formation

SARS-ACE2 internalization by endocytosis

Viral budding

SARS may be able to hijack human cyclophilin A to enhance its attachment to CD147 and increase infectivity within patient body.

SARS inhibits immune response

SARS inhibits innate immunity – SARS can inhibit cell anti-viral response using its PLpro protease and ORF9b. SARS blocks three major double-stranded RNA sensors in a cell, thus disabling cellular innate immunity. Innate immunity is one of the most ancient mechanisms in Eukaryotic organisms to fight viral and bacterial infections. Human proteins involved in innate immunity are similar to innate immunity proteins in insects. Only SARS-CoV has ORF9b, COVID19 (SARS-CoV2) seems to have novel ORF10 instead.

SARS ORF6 inhibits IFN production – Another way SARS inhibits innate response is using ORF6 protein to block nuclear translocation of transcription factors responsible for interferon production

SARS inhibits BST2 – antiviral tetherin that inhibits viral particle release

NSP1 inhibits protein synthesis and activates immunophilins – SARS-CoV can inhibit host cell protein synthesis. However, protein synthesis is necessary to make viral proteins for virus packaging. Therefore SARS must be able to regulate this process somehow.

SARS-Cov NSP1 also can bind peptidyl-prolyl isomerease (immunophilins) to inhibit mTOR kinase and NFAT transcription factor. mTOR inhibition leads to activation of autophagy and NFAT inhibition may lead to inhibition of cellular immunity after SARS-CoV infection of T-cells.

Also checkout SARS-CoV2 NSP1 mystery interactions with DNA polymerase according to Gordon et al 2020. Can SARS-CoV2 cause cell-cycle arrest?

COVID19 – host interactions

Interactions between SARS-CoV2 proteins and human proteins were either predicted from known SARS-CoV orthologous interactions as described in Pfefferle et al 2011Zhou et al 2020Srinivasan et al 2020Guzzi et al 2020 or imported from Gordon et al 2020.

NSP1 interactions

NSP2 inhibits apoptosis (hypothesis) SARS-Cov NSP2 interaction with prohibitin, which may improve mitochondrial biogenesis and cell survival. This may means that SARS turn the host cell into zombie that lives longer and therefore makes more virus particles.

Interactions for: NSP2NSP3 (PL-pro)NSP4NSP5 (Mpro)NSP6NSP7NSP8NSP9NSP10NSP11NSP12NSP13;

ORF3b, ORF7b interactionsORF7a interactions

ORF8 interactions may increase stability of HIF1A protein and inhibit Endoplasmic-reticulum-associated protein degradation (ERAD)

ORF10 improves cell survival (hypothesis) by increasing stability of HIF1A

S (spike) protein interactions – In addition to ACE2 Spike protein may bind 6 other proteins and 2 human metabolites. Make sure to check supporting references – some of these interactions are predicted from MERS protein interactions or computer docking experiments.

N protein interactions

M protein interations

SARS Viroporins (ORF3a, E) – SARS genome encodes two ion channels that activate NLRP inflamasome and down-regulated interferon receptor. Reconstruction of this pathway allowed to re-purpose one more drug, ponatinib, for COVID-19 and suggest new targets – NEK7 and RIPK3. Because ponatinib has a lot of adverse reactions, more lead compounds for drug development can be found in Reaxys.

Cytokine storm

Aberrant macrophage activation in COVID19 – this pathways is entirely built using Liao et al 2020 article from medArxiv.

ACE2 biology

Renin-Angiotensin system to regulate blood pressure

Role of ACE2 in the gut

This article was originally published in my Linkedin Articles. Feel free to contact me if you would like to discuss these models further.  

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