Target 21: corona_TMPRSS2_v1

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Profile Natalia
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Message 1760 - Posted: 17 Nov 2022, 13:21:56 UTC

Dear Participants,

TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal human tracts. It is a cofactor in SARS-CoV-2 entry, and primes viral proteins. Namely, TMPRSS2 cleaves the viral Spro to expose the fusion peptide for cell entry. We are therefore examining TMPRSS2 as a promising strategy to block viral infection in a host-directed therapeutic and/or prophylactic manner. This work is also a a part of larger viral-host protease inhibition study campaign.

With best wishes,
Team SiDock@home
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mikey
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Message 1763 - Posted: 18 Nov 2022, 2:58:16 UTC - in response to Message 1760.  

Dear Participants,

TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal human tracts. It is a cofactor in SARS-CoV-2 entry, and primes viral proteins. Namely, TMPRSS2 cleaves the viral Spro to expose the fusion peptide for cell entry. We are therefore examining TMPRSS2 as a promising strategy to block viral infection in a host-directed therapeutic and/or prophylactic manner. This work is also a a part of larger viral-host protease inhibition study campaign.

With best wishes,
Team SiDock@home


Does that mean more tasks are coming or is this more of a report on work that's been completed and that the results are now being tested?
Either way it sounds like GREAT news!!!
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PeteC

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Message 1768 - Posted: 24 Nov 2022, 14:18:16 UTC - in response to Message 1760.  

Hi Natalia and the SiDock Team. I am not familiar with the medical / chemical wording used ( hereafter called Technical Voodoo) in this message. WOuld it be possible to have these news snippets translated into simple terms ? I know it can sometimes be difficult to find substitute words but "keeping it simple" is always a good philosophy to follow.

Kind regards and keep up the good work,
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Aurum
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Message 1783 - Posted: 6 Jan 2023, 15:31:07 UTC - in response to Message 1760.  
Last modified: 6 Jan 2023, 15:35:45 UTC

TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal human tracts. It is a cofactor in SARS-CoV-2 entry, and primes viral proteins. Namely, TMPRSS2 cleaves the viral Spro to expose the fusion peptide for cell entry. We are therefore examining TMPRSS2 as a promising strategy to block viral infection in a host-directed therapeutic and/or prophylactic manner.
My attempt to translate this Technical Voodoo speak into lay language:

TMPRSS2 is a protein that is naturally found living in the cell wall of your guts and lungs. It is an enzyme that cuts the viral protein S2 at a certain serine amino acid sequence in the S2 active site. First the SARS-CoV-2 virus binds the ACE2 receptor that naturally lives in the cell membrane of many human cells. Then TMPRSS2 bumps into the bound ACE2 molecule and cuts the viral S2 allowing the virus membrane to merge with the cell membrane and dump the virus contents inside the cell where the human cellular machinery makes many many copies of the virus and spews them out into your blood and fluids to spread. If we can find a small molecule that can bind to TMPRSS2 in such a way that it prevents cutting S2 then the virus will be stuck on the outside of the cell and is not copied. This would greatly slow down Covid progression. It is not likely to stop the disease entirely since it still allows for endosomal entry as shown in the Nature Figure 3 below.

https://en.wikipedia.org/wiki/Transmembrane_protein#/media/File:Group_1_and_2_transmembrane_protein.png
https://www.nature.com/articles/s41580-021-00418-x/figures/3
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hoarfrost
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Message 1788 - Posted: 9 Jan 2023, 7:40:09 UTC - in response to Message 1763.  

Does that mean more tasks are coming or is this more of a report on work that's been completed and that the results are now being tested?
Either way it sounds like GREAT news!!!

Yes, it's a new tasks (now is are mostly completed) and results from new target expand a set of compounds for testing in the laboratory.

WOuld it be possible to have these news snippets translated into simple terms?

It's a good idea, we tried to write a tiny explanation, but more explanations and more pictures can add more interest, I think.

TMPRSS2 is a protein that is naturally found living in the cell wall of your guts and lungs. It is an enzyme that cuts the viral protein S2 at a certain serine amino acid sequence in the S2 active site. First the SARS-CoV-2 virus binds the ACE2 receptor that naturally lives in the cell membrane of many human cells. Then TMPRSS2 bumps into the bound ACE2 molecule and cuts the viral S2 allowing the virus membrane to merge with the cell membrane and dump the virus contents inside the cell where the human cellular machinery makes many many copies of the virus and spews them out into your blood and fluids to spread. If we can find a small molecule that can bind to TMPRSS2 in such a way that it prevents cutting S2 then the virus will be stuck on the outside of the cell and is not copied. This would greatly slow down Covid progression. It is not likely to stop the disease entirely since it still allows for endosomal entry as shown in the Nature Figure 3 below.
https://en.wikipedia.org/wiki/Transmembrane_protein#/media/File:Group_1_and_2_transmembrane_protein.png
https://www.nature.com/articles/s41580-021-00418-x/figures/3

I will also add that by slowing down the virus replication, we will give the immune system time to produce the response.
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Marko Jukic
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Message 1792 - Posted: 9 Jan 2023, 18:09:05 UTC

Dear SiDock@home community,

We are grateful for your interest! Indeed, TMPRSS2, or transmembrane protease, serine 2 is a protease on host cells. In contrast to targeting viral proteins, herein, we target a host protein (host-directed approaches) that is responsible for viral Spike protein processing and, ultimately, viral entry into host (our /human) cells. The potential inhibitor compounds herein could hinder viral entry and be useful as probes for viral studies. Some non-selective compounds are already known, but additional insights are welcome.

Thank You All !!!
Marko

p.s. We are still delving into SARS-CoV-2 due to future work, however, in the future of SiDock@home, expect also other targets to be investigated in this wonderful drug design community project.
p.p.s.
Thanks also, Aurum for the help and the link to the article: Nature Reviews Molecular Cell Biology volume 23, pages 3–20 (2022). Also, some excellent work herein: Nature volume 605, pages340–348 (2022).
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hoarfrost
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Message 1793 - Posted: 9 Jan 2023, 18:40:18 UTC

Small notice: non-selective compound - is a compound that react with others, non-targeted molecules of proteins.
It is not difficult to find a compound, that kills the virus. But this compound must be safe for human. Sulfuric acid is ruthless virus eraser, but it kills everything around.
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