Home health remedies Elsevier models for COVID19 bio-molecular mechanisms

Elsevier models for COVID19 bio-molecular mechanisms

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

Pathways that were built to re-purpose existing drugs against COVID19 infection are now available in open access. These pathways were built using data from Elsevier Pathway Studio and were discussed previously in my blog. We now have identified at least three more strategies for drug re-purposing in addition to three strategies discussed in the blog: inhibition of host proteases, inhibition of endocytosis, inhibition of viral enzymes (proteases and replicase). Continue below for more information and links to the pathways.

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.

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 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?

ACE2 biology

Renin-Angiotensin system to regulate blood pressure

Role of ACE2 in the gut

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