Fight the COVID-19 with Eterna

https://www.preprints.org/manuscript/202001.0358/v3
“By using molecular docking, we proposed that the five natural compounds, including baicalin, Scutellarin, Hesperetin, glycyrrhizin and Nicotianamine (Figure 1) are potential compounds that target the ACE2 receptor and exert anti-virus effects for preventing 2019-nCoV infection.”

So my question is can the DNA sequence/genes for these compounds be determined and then RNAs related to them and the ACE2 receptor be backed out of these to find common attack points?

[I note that Baicalin was one of the top hits in the giant AI-machine learning search.]

Can you give link to the AI-machine learning search effort?

Rapid Identification of Potential Inhibitors of SARS-CoV-2 Main Protease
by Deep Docking of 1.3 Billion Compounds

https://s3-eu-west-1.amazonaws.com/pstorage-chemrxiv-899408398289/21739317/SM_1.pdf

https://www.researchgate.net/profile/Francesco_Gentile8/publication/339365607_Rapid_Identification_o…

https://s3-eu-west-1.amazonaws.com/pstorage-chemrxiv-899408398289/21739317/SM_1.pdf

_ _

Oops! I think I miss attributed the baicalin reference above.
But I made the links to the giant AI-machine learning search paper below in the forum.

New York Times published an article yesterday explaining the function of each protein and listing the RNA code for each protein. Could be useful for making puzzles.
https://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protein.html

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Nice NYT article with all the proteins and if known their functions.
https://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protei…

Dual effect of nitric oxide on SARS-CoV replication: Viral RNA production and palmitoylation of the S protein are affected.
https://www.ncbi.nlm.nih.gov/pubmed/19800091

I find LOTS of NOx, iNOS activity in my explorations of the RNA.

Get a solid foundation on virusses. Here is an ongoing university semester in virology. Even better this education is not just free, it is also excellent. 

 

Characterization of spike glycoprotein ofSARS-CoV-2 on virus entry and its immunecross-reactivity with SARS-CoV

https://www.nature.com/articles/s4146…

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein
https://reader.elsevier.com/reader/sd…

another TMPRSS2 paper
ArticleSARS-CoV-2 Cell Entry Depends on ACE2 andTMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor
https://www.cell.com/cell/pdf/S0092-8…

Dark Proteome of Newly Emerged SARS-CoV-2 in Comparison with Human and Bat Coronaviruses
https://www.biorxiv.org/content/10.11…

This makes proteins 7a and N look like good candidates for focus of effort:

Global profiling of SARS-CoV-2 specific IgG/ IgM responses of convalescents using a proteome microarray
https://www.medrxiv.org/content/10.1101/2020.03.20.20039495v1

“The results suggest that at the convalescent phase 100% of patients had IgG/ IgM responses to SARS-CoV-2, especially to protein N, S1 but not S2.”

“Besides protein N and S1, significant antibody responses to ORF9b and NSP5 were also identified. In-depth analysis showed that the level of S1 IgG positively correlate to age and the level of LDH (lactate dehydrogenase), especially for women, while the level of S1 IgG negatively correlate to Ly% (Lymphocyte percentage).”

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Coronavirus: Genome packing signal

“The assembly of infectious coronavirus particles requires the selection of viral genomic RNA from a cellular pool that contains an abundant excess of non-viral and viral RNAs. Among the seven to ten specific viral mRNAs synthesized in virus-infected cells, only the full-length genomic RNA is packaged efficiently into coronavirus particles. Studies have revealed cis-acting elements and trans-acting viral factors involved in the coronavirus genome encapsidation and packaging. Understanding the molecular mechanisms of genome selection and packaging is critical for developing antiviral strategies and viral expression vectors based on the coronavirus genome.”

https://en.wikipedia.org/wiki/Coronavirus

One more thing I took note of, are the cis-acting (before the gene) and trans-acting (outside the gene) viral factors. Now I wonder if some of the structures of the conserved sequences in your paper, are such factors?

Like how many of them are before a gene?

I also wonder if the job of some of them is to slow down the ribosome after a gene is made, so that the specific gene part just made, can get cut.

I am also searching for an overview of the content of the coronavirus genome. So I could compare to the numbers in your paper.

_“In common with the genomes of all other RNA viruses, coronavirus genomes contain cis-acting RNA elements that ensure the specific replication of viral RNA by a virally encoded RNA-dependent RNA polymerase. The embedded cis-acting elements devoted to coronavirus replication constitute a small fraction of the total genome, but this is presumed to be a reflection of the fact that coronaviruses have the largest genomes of all RNA viruses. The boundaries of cis-acting elements essential to replication are fairly well-defined, and the RNA secondary structures of these regions are understood. However, how these cis-acting structures and sequences interact with the viral replicase and host cell components to allow RNA synthesis is not well understood.” (_Also from the same wikiarticle.)

I took note that only the full-length genome of viral RNA is packaged. So it is really used as one giant mRNA in the host ribosomes.

Rhiju: There is a hypothesis that UUYCGU apical loops (‘hairpins’) in SL5 in the 5’ UTR are packaging signals (‘cis acting factors’)

That’s for SARS Coronavirus and some other beta coronaviruses

I haven’t yet seen experiments that test that idea — keep your eyes open.

here’s the paper with the original proposal, from 2010:

Group-specific structural features of the 5’-proximal sequences of coronavirus genomic RNAs

Eli: 5’ UTR of the coronavirus as taken from your preprint:

5’ UTR image with Chen/Olsthoorn genomesignal hairpins highlighted

Notice the two marked loops at the bottom of the image.

A partial in the sequence is also on the pseudoknot of the frameshift:

Pseudoknot frameshift

At position 200-205 and 238-243

Eli: Actually this looks exactly like this one:

Conserved hexaloops from the Chen/Olsthoorns paper

Rhiju das: yes exactly

3 conserved endloops

I wonder if there is anything these UUUCGU sequences are complementary to.

Eli: These two mostly pyrimidine stretches, kind of reminds me of this:

iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution

I wonder if the other coronaviruses show the same 4 way junction structure, as above?

Rhiju das: the Chen/Olsthoorn paper shows the SL5 for lots of coronaviruses — the 4WJ is unique to SARS/SARS-II and closely related.

Eli 4WJ?

Ah :slight_smile: (4 way junction)

So structure and hairpin loops are conserved. While longer stretches of sequences for this area are not. Ok, I can see that 80-197 and 120-237 are also pretty conserved according to your paper.

Now I wonder what the packaging signals for DNA looks like. Assuming there are some too.

I mean, what starts the assembly of histones? Or nucleoproteins

I wonder what would happen if one threw the 5’ UTR in a test tube with a lot of nucleoproteins.

Rhiju: Thumbs up

Eli: And I see that Chen/Olsthoorn would also like to know that:

“Future experiments should also verify whether the conserved UUYCGU motifs in SL5 function as PS in group Iand II CoVs by interacting with nucleocapsid and/or membrane proteins.”

Eli: If these UUUCGU hairpin loops really are a packing signal for the viral genome, I wonder if they could be used as a medical target. I mean, no packaging, no further infection. The 6 nt hairpin loops looks suspiciously like one half part of a kissing loop. I wonder if such a partner could be made to target the hairpin loop and if this would affect replication of coronavirus. Alternatively perhaps an RNA aptamer could be evolved to target this region.

Alternatively, is any protein or drug known to bind to such a sequene/structure?

One more thing I have been wondering about. If the viral corona genome can be seen like a sort of operon.

I mean if not all proteins have to be made at the same time, it would make sense to have an operon to orchestrate when what is made.

A normal operon has a promotor and operator. The operator can be down regulated. Not sure coronavirus is interested in downregulating itself. So this may not be there.

On gene regulation and timing I recall reading that the M, N and S proteins were made and followed the same pathway.

“The viral structural proteins S, E, and M move along the secretory pathway into the Golgi intermediate compartment.”

https://en.wikipedia.org/wiki/Coronavirus

Since in e.coli, the lac operon is activated by lactase, I have started wondering about viral metabolism. What energy source, like atp, lipids, glucose, steroids etc it prefers. And if such an energy source could be an activator.

I have read a bit on and I have found that it is known that viruses up and downregulates the metabolism of the host. Plus that certain viruses have specific preferences. I have read this paper, which I find very interesting:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3004434/

Since in e.coli, the lac operon is activated by lactase, I have started wondering about viral metabolism. What energy source, like atp, lipids, glucose, steroids etc it prefers. And if such an energy source could be an activator.

I have yet to find anything in relation to coronavirus and their metabolism. I would like to know what would happen with lungcells infected with SARS-2 and put on different diets.

Eli: I have found several papers on covid that says that coronavirus upregulates an inflammation pathway.

Rhiju das: 

> “Alternatively, is any protein or drug known to bind to such a sequene/structure?”

I’ve been wondering the same thing

>A normal operon has a promotor and operator. The operator can be down regulated. Not sure coronavirus is interested in downregulating itself. So this may not be there.

Its there. The virus has to change the transcription of its full genome vs. subgenomic RNAs to switch between replication (early) and then packaging (late). Lots of empirical information known, but unclear how the different amounts of RNA are turned on/off — many have hypothesized that the ‘logic’ is embedded in the structures of these elements

Gene regulation and the order of the operon by Amoeba Sisters

I have later dropped the idea that the S, E and M proteins are in an operon, since they are not present in coronavirus in the same amount. 

We demonstrate here that anti-Spike immune serum, while inhibiting viral entry in a permissive cell line, potentiated infection of immune cells by SARS-CoV Spike-pseudotyped lentiviral particles, as well as replication-competent SARS corona-virus. Antibody-mediated infection was dependent on Fcy receptor II but did not use the endosomal/lysosomal pathway utilized by angiotensin I converting enzyme 2 (ACE2), the accepted receptor for SARS-CoV. This suggests that ADE of SARS-CoV utilizes a novel cell entry mechanism into immune cells.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187504/pdf/zjv10582.pdf

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The implications for this pandemic are interesting in this non-pandemic article on memory.

“Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons.”

“Arc is derived from a vertebrate lineage of Ty3/gypsy retrotransposons, which are also ancestors to retroviruses.”

Maybe a built-in way to make our mRNA vaccine?

https://getpocket.com/explore/item/all-your-memories-are-stored-by-one-weird-ancient-molecule?utm_so…

The Neuronal Gene Arc Encodes a Repurposed Retrotransposon Gag Protein that Mediates Inter-cellular RNA Transfer
https://www.cell.com/cell/pdf/S0092-8674(17)31504-0.pdf

Citrus flavonoid hesperidin may prove a dietary intervention possible.

Revealing the Potency of Citrus and Galangal Constituents
to Halt SARS-CoV-2 Infection

[https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=8&ved=2ahUKEwj...](https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=8&ved=2ahUKEwjopr_V0NzoAhXrYN8KHVulANgQFjAHegQICBAB&url=https%3A%2F%2Fwww.preprints.org%2Fmanuscript%2F202003.0214%2Fv1%2Fdownload&usg=AOvVaw0poMYV4RxAQa1hdrojs5jW "Link httpswwwgooglecomurlsatrctjqesrcssourcewebcd8ved2ahUKEwjopr\_V0NzoAhXrYN8KHVulANgQFjAHegQICBABurlhttps3A2F2Fwwwpreprintsorg2Fmanuscript2F20200302142Fv12FdownloadusgAOvVaw0poMYV4RxAQa1hdrojs5jW")

Eli: I have just got very fascinated with the MHC class 1 antigen presentation on cells. I wonder if this can get used for vaccination against coronavirus? 

Rhiju : Yes — that’s the basis for our MEV challenges…

Eli: Oh, hehe

Ok, so here comes some introduction to MHC class 1: 

IBiology introduction

Immunology - MCH I processing Armando Hasudugan

Podcast: This Week in Virology TWiV 597: A lot of immunology and some COVID-19 with Jon Yewdell

Paper: MHC class I-presented peptides and the DRiP hypothesis