14 ms·

Edit: contact made, thank you! If anyone is reading this with connections to the Gates Foundation: Please contact Dr. Robert Kruse at John Hopkins. https://twi

Edit: contact made, thank you! If anyone is reading this with connections to the Gates Foundation: Please contact Dr. Robert Kruse at John Hopkins. https://twitter.com/RobertLKruse https://twitter.com/RobertLKruse. I have been trying to get in touch with people at Gates. This announcement unfortunately features no contact email address :( Dr. Kruse is developing an extremely promising therapeutic, ACE2-fc, which will both neutralize the virus and treat the symptoms of the disease. It has been shown to work in vitro; variants have been tested in animals models; and its been through Phase II human trials for a different indication. A variant of the therapy, soluble ACE2, is being trialed in humans now in China. Details on the approach can be found in his paper here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/ see "ACE2 immunoadhesin strategy"

deleted 7y ago
[deleted]
pkaye 7y ago
For you know if the ACE2 genes mentioned with relation to coronavirus have anything to do with ACE inhibitors and ARB inhibitors?
- wbl 7y ago
  ACE is the enzyme that ACE inhibitors inhibit. Why is it expressed in the lungs? I have no clue.
  - deleted 7y ago
    [deleted]
  - epmaybe 7y ago
    That's where Angiotensin I (ACE = Angiotensin Converting Enzyme) is converted to Angiotensin II, which acts on tons of blood vessels to increase blood pressure. That's essentially why ACE inhibitors have a blood pressure effect. On top of that, Bradykinin is an inflammatory mediator that is degraded by ACE. It's heavily implicated in the side effect ACE inhibitors have of dry cough.
    - wbl 7y ago
      But why the lungs and not the liver?
      - epmaybe 7y ago
        Now that is a very interesting question! Unfortunately, I don't think that we have a complete answer. A couple of notes, that perhaps can provide some perspective: 1. lungs are highly vascularised areas with a large amount of vascular endothelium, making them a great location to express ACE if you want to convert as much angiotensin I as you can in the space of a heartbeat (which you'd like to do if your blood pressure dropped, for example). 2. ACE is not specific for angiotensin, it acts on a variety of peptides. Bradykinin is a good example as it can provide more perspective on why ACE is expressed mainly in lung tissue. Bradykinin acts to contract smooth muscle in your airways. Thus, degrading bradykinin via ACE is a good way to improve your breathing.
- jokowueu 7y ago
  Your are correct It's related to ACE inhibitors .
- philipn 7y ago
  It is related, but it's pretty complicated. For some information on this and the potential relationship, see my twitter account: https://twitter.com/__philipn__ https://twitter.com/__philipn__
- forkexec 7y ago
  The latest is that ACE2 and TMPRSS2 are both needed to infect humans. There are already two compounds identified to block these pathways, one of which is already a medication used in Japan. Both are very safe with huge LD50's.
  - pkaye 7y ago
    So would there be an additional risks from coronavirus to those taking ACE or ARB inhibitors?
    - ignoramous 7y ago
      See a recent albeit heated discussion here: https://news.ycombinator.com/item?id=22500063 https://news.ycombinator.com/item?id=22500063
- dreamcompiler 7y ago
  IIRC, conventional ACE inhibitors don't inhibit ACE2, which would be be needed to fight COVID-19.
- fxtentacle 7y ago
  Apparently, a serine protease inhibitor works. I didn't hear anything about regular ace inhibitors. https://www.dpz.eu/en/home/single-view/news/die-vermehrung-von-sars-coronavirus-2-im-menschen-verhindern.html https://www.dpz.eu/en/home/single-view/news/die-vermehrung-v...
- delhanty 7y ago
  This may be relevant: there's a recent (3rd March) hypothesis due to Rami Sommerstein from Department of Infectious Diseases, Bern University Hospital [0] that ACE inhibitors are a potential risk factor for fatal Covid-19 in those patients taking ACE inhibitors for hypertension/diabetes/cardiovascular disease: >The largest Chinese study with 44,672 confirmed cases of Covid-19 shows a high overall case fatality rate (CFR) of 2.3% [2]. Important co-morbidities are hypertension (CFR 6.0%), diabetes (CFR 7.3%), cardiovascular disease (CFR 10.5%) and age >70 (CFR 10.2%) [2]. Similar co-morbidities were noted for the SARS outbreak in 2003. > ... >On the one hand, it has been shown that the Covid-19 agent (also known as SARS-CoV-2), uses the SARS-COV receptor angiotensin converting enzyme (ACE) 2 for entry into target cells [4]. The interface between ACE2 and the viral spike protein SARS-S has been elucidated and the efficiency of ACE2 usage was found to be a key determinant of SARS-CoV transmissibility [4]. > >On the other hand, it could be shown in animal experiments that both the ACE-inhibitor lisinopril and the angiotensin-receptor blocker losartan can significantly increase mRNA expression of cardiac ACE2 (5-fold and 3-fold, respectively) [5]. Further, losartan also significantly increases cardiac ACE2 activity [5]. Edit: thank you philipn for your twitter link. [0] https://www.bmj.com/content/368/bmj.m810/rr-2 https://www.bmj.com/content/368/bmj.m810/rr-2
  - philipn 7y ago
    Please see my twitter account for lots on this. I'm in contact with a bunch of top researchers on this topic (renin-angiotensin system; ACE2/Ang 1-7/Mas axis; ARB usage for viral diseases) and will be posting a summary update soon: https://twitter.com/__philipn__/status/1235756671852589056 https://twitter.com/__philipn__/status/1235756671852589056 It may be the other way around: ACEi/ARB may be protective. HTN without ACEi/ARB would be non-protective, potentially so much so that it skews the group fatality numbers. This is because people with HTN have a different renin-angiotensin system profile: more AT1R, less AT2R, more ACE, potentially less ACE2. This is being looked at now. But the key is that in every study ever done on viral lung disease, etc, AT1R blockade was highly beneficial, and we know that ACE2-knockout basically screws up lungs, makes viral lung disease way worse, etc. Please see my twitter posts. The virus eats up ACE2, downregulating it as it binds. This would have delirious effects. Check out the linked "essential reading" twitter post. Will be posting a summary to my twitter soon.
justAnotherNET 7y ago
If this makes a difference, please include me in the screenshot senpai
jokowueu 7y ago
Do you know of any one site that provides a comprehensive list of all the studies/drugs regarding covid-19 ?
- philipn 7y ago
  List of repurposed drugs (not comprehensive) https://www.nature.com/articles/d41587-020-00003-1 https://www.nature.com/articles/d41587-020-00003-1 Review of small molecule therapies (not comprehensive): https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed https://blogs.sciencemag.org/pipeline/archives/2020/03/06/co...
sandGorgon 7y ago
you have no idea how happy this makes me (I'm the original OP). I think this is the best thing i achieved all year.
- simonebrunozzi 7y ago
  You should feel proud. Thanks!
jacobush 7y ago
Depending on how things turn out in the end, this may be the most important thing yCombinator has achieved, ever.
- onion2k 7y ago
  We'll never know. If it works then Covid-19 will be a footnote in history, a temporary problem that was quickly solved. We won't know if it would have become an extinction-threatening event or if it would have fizzled out on it's own, or anything in between. If it doesn't work then YC's input wasn't important and didn't help.
  - slimed 7y ago
    This take is too pessimistic. Eventually we will have enough data to project what could have happened without treatments like this. We will know the rate of infection, the rate of death without treatment, etc. There will be many different groups globally trying to find out these answers and apply them to preventing future pandemics.
- cmauniada 7y ago
  I mean, I get where you are coming from but it still is a huge stretch to make a blanket statement like that.
dharma1 7y ago
edit: looks like it is. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/#ref-60 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/#ref-60 Is this the soluble ACE2 mentioned? https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologics-covid-19-trial/ https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologi... https://pipelinereview.com/index.php/2020022673884/Proteins-and-Peptides/APEIRONs-respiratory-drug-product-to-start-pilot-clinical-trial-to-treat-coronavirus-disease-COVID-19-in-China.html https://pipelinereview.com/index.php/2020022673884/Proteins-... https://connect.myesr.org/course/novel-coronavirus-outbreak-experience-and-challenges-in-imaging-and-beyond/ https://connect.myesr.org/course/novel-coronavirus-outbreak-... It was initially discovered and developed during the SARS epidemic - https://www.nature.com/articles/nm1267 https://www.nature.com/articles/nm1267
davidw 7y ago
Work like this is another reason to shut everything non-essential the hell down. It gives people time to do important work that could save lives. https://www.theatlantic.com/ideas/archive/2020/03/coronavirus-cancel-everything/607675/ https://www.theatlantic.com/ideas/archive/2020/03/coronaviru...
martyvis 7y ago
Don't researchers like this just go to WHO for support and assistance? This is a list of candidate vaccines. https://www.who.int/blueprint/priority-diseases/key-action/list-of-candidate-vaccines-developed-against-sars.pdf https://www.who.int/blueprint/priority-diseases/key-action/l...
iskander 7y ago
I just started working on the complementary side of the spike RBD-ACE2 interaction, making an aerosol of RBD peptide fragments to outcompete the virus for entry. This work is based on B-cell epitope mapping of SARS patients and subsequent identification of ACE2 binding peptides like: https://www.sciencedirect.com/science/article/pii/S0166354211005481 https://www.sciencedirect.com/science/article/pii/S016635421... I'm the "dry lab" side of this project -- looking for peptide candidates. My other collaborators at UNC are going to do formulate the aerosol and test for safety in mice. Normally this would be a very early stage in drug development, but it seems like we have to move quickly. So similar shout out to the Gates Foundation folks -- if you're interested in this approach email alex.rubinsteyn@unc.edu
bionhoward 7y ago
I’m not a doctor, but fusing a complement activator to a natural enzyme and megadosing it is a horrible idea because it’s gonna trigger complement activation in the context of a self protein, which could cause major autoimmunity, and ACE2 overload is gonna overactivate the angiotensin-aldosterone axis and deactivate renin via negative feedback, screw up your electrolytes which could cause arrhythmias, and give you high blood pressure. To avoid side effects, a therapy ought to be as orthogonal as possible to natural systems. A high dose of a hormone activator smushed together with an immune activator is definitely not orthogonal to natural systems. More useful to focus on genomic smart bombs like CRISPR Cas13 ( cough, https://github.com/bionicles/coronavirus https://github.com/bionicles/coronavirus ) or RNAi because they’re way, way, way, less likely to have side effects, they can last forever, can easily be retargeted to future germs hella quick, etc etc

deleted 7y ago

[deleted]

pkaye 7y ago

For you know if the ACE2 genes mentioned with relation to coronavirus have anything to do with ACE inhibitors and ARB inhibitors?

wbl 7y ago
ACE is the enzyme that ACE inhibitors inhibit. Why is it expressed in the lungs? I have no clue.
- deleted 7y ago
  [deleted]
- epmaybe 7y ago
  That's where Angiotensin I (ACE = Angiotensin Converting Enzyme) is converted to Angiotensin II, which acts on tons of blood vessels to increase blood pressure. That's essentially why ACE inhibitors have a blood pressure effect. On top of that, Bradykinin is an inflammatory mediator that is degraded by ACE. It's heavily implicated in the side effect ACE inhibitors have of dry cough.
  - wbl 7y ago
    But why the lungs and not the liver?
    - epmaybe 7y ago
      Now that is a very interesting question! Unfortunately, I don't think that we have a complete answer. A couple of notes, that perhaps can provide some perspective: 1. lungs are highly vascularised areas with a large amount of vascular endothelium, making them a great location to express ACE if you want to convert as much angiotensin I as you can in the space of a heartbeat (which you'd like to do if your blood pressure dropped, for example). 2. ACE is not specific for angiotensin, it acts on a variety of peptides. Bradykinin is a good example as it can provide more perspective on why ACE is expressed mainly in lung tissue. Bradykinin acts to contract smooth muscle in your airways. Thus, degrading bradykinin via ACE is a good way to improve your breathing.
jokowueu 7y ago
Your are correct It's related to ACE inhibitors .
philipn 7y ago
It is related, but it's pretty complicated. For some information on this and the potential relationship, see my twitter account: https://twitter.com/__philipn__ https://twitter.com/__philipn__
forkexec 7y ago
The latest is that ACE2 and TMPRSS2 are both needed to infect humans. There are already two compounds identified to block these pathways, one of which is already a medication used in Japan. Both are very safe with huge LD50's.
- pkaye 7y ago
  So would there be an additional risks from coronavirus to those taking ACE or ARB inhibitors?
  - ignoramous 7y ago
    See a recent albeit heated discussion here: https://news.ycombinator.com/item?id=22500063 https://news.ycombinator.com/item?id=22500063
dreamcompiler 7y ago
IIRC, conventional ACE inhibitors don't inhibit ACE2, which would be be needed to fight COVID-19.
fxtentacle 7y ago
Apparently, a serine protease inhibitor works. I didn't hear anything about regular ace inhibitors. https://www.dpz.eu/en/home/single-view/news/die-vermehrung-von-sars-coronavirus-2-im-menschen-verhindern.html https://www.dpz.eu/en/home/single-view/news/die-vermehrung-v...
delhanty 7y ago
This may be relevant: there's a recent (3rd March) hypothesis due to Rami Sommerstein from Department of Infectious Diseases, Bern University Hospital [0] that ACE inhibitors are a potential risk factor for fatal Covid-19 in those patients taking ACE inhibitors for hypertension/diabetes/cardiovascular disease: >The largest Chinese study with 44,672 confirmed cases of Covid-19 shows a high overall case fatality rate (CFR) of 2.3% [2]. Important co-morbidities are hypertension (CFR 6.0%), diabetes (CFR 7.3%), cardiovascular disease (CFR 10.5%) and age >70 (CFR 10.2%) [2]. Similar co-morbidities were noted for the SARS outbreak in 2003. > ... >On the one hand, it has been shown that the Covid-19 agent (also known as SARS-CoV-2), uses the SARS-COV receptor angiotensin converting enzyme (ACE) 2 for entry into target cells [4]. The interface between ACE2 and the viral spike protein SARS-S has been elucidated and the efficiency of ACE2 usage was found to be a key determinant of SARS-CoV transmissibility [4]. > >On the other hand, it could be shown in animal experiments that both the ACE-inhibitor lisinopril and the angiotensin-receptor blocker losartan can significantly increase mRNA expression of cardiac ACE2 (5-fold and 3-fold, respectively) [5]. Further, losartan also significantly increases cardiac ACE2 activity [5]. Edit: thank you philipn for your twitter link. [0] https://www.bmj.com/content/368/bmj.m810/rr-2 https://www.bmj.com/content/368/bmj.m810/rr-2
- philipn 7y ago
  Please see my twitter account for lots on this. I'm in contact with a bunch of top researchers on this topic (renin-angiotensin system; ACE2/Ang 1-7/Mas axis; ARB usage for viral diseases) and will be posting a summary update soon: https://twitter.com/__philipn__/status/1235756671852589056 https://twitter.com/__philipn__/status/1235756671852589056 It may be the other way around: ACEi/ARB may be protective. HTN without ACEi/ARB would be non-protective, potentially so much so that it skews the group fatality numbers. This is because people with HTN have a different renin-angiotensin system profile: more AT1R, less AT2R, more ACE, potentially less ACE2. This is being looked at now. But the key is that in every study ever done on viral lung disease, etc, AT1R blockade was highly beneficial, and we know that ACE2-knockout basically screws up lungs, makes viral lung disease way worse, etc. Please see my twitter posts. The virus eats up ACE2, downregulating it as it binds. This would have delirious effects. Check out the linked "essential reading" twitter post. Will be posting a summary to my twitter soon.

justAnotherNET 7y ago

If this makes a difference, please include me in the screenshot senpai

jokowueu 7y ago

Do you know of any one site that provides a comprehensive list of all the studies/drugs regarding covid-19 ?

philipn 7y ago
List of repurposed drugs (not comprehensive) https://www.nature.com/articles/d41587-020-00003-1 https://www.nature.com/articles/d41587-020-00003-1 Review of small molecule therapies (not comprehensive): https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed https://blogs.sciencemag.org/pipeline/archives/2020/03/06/co...

sandGorgon 7y ago

you have no idea how happy this makes me (I'm the original OP). I think this is the best thing i achieved all year.

simonebrunozzi 7y ago
You should feel proud. Thanks!

jacobush 7y ago

Depending on how things turn out in the end, this may be the most important thing yCombinator has achieved, ever.

onion2k 7y ago
We'll never know. If it works then Covid-19 will be a footnote in history, a temporary problem that was quickly solved. We won't know if it would have become an extinction-threatening event or if it would have fizzled out on it's own, or anything in between. If it doesn't work then YC's input wasn't important and didn't help.
- slimed 7y ago
  This take is too pessimistic. Eventually we will have enough data to project what could have happened without treatments like this. We will know the rate of infection, the rate of death without treatment, etc. There will be many different groups globally trying to find out these answers and apply them to preventing future pandemics.
cmauniada 7y ago
I mean, I get where you are coming from but it still is a huge stretch to make a blanket statement like that.

dharma1 7y ago

edit: looks like it is. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/#ref-60 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/#ref-60 Is this the soluble ACE2 mentioned? https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologics-covid-19-trial/ https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologi... https://pipelinereview.com/index.php/2020022673884/Proteins-and-Peptides/APEIRONs-respiratory-drug-product-to-start-pilot-clinical-trial-to-treat-coronavirus-disease-COVID-19-in-China.html https://pipelinereview.com/index.php/2020022673884/Proteins-... https://connect.myesr.org/course/novel-coronavirus-outbreak-experience-and-challenges-in-imaging-and-beyond/ https://connect.myesr.org/course/novel-coronavirus-outbreak-... It was initially discovered and developed during the SARS epidemic - https://www.nature.com/articles/nm1267 https://www.nature.com/articles/nm1267

davidw 7y ago

Work like this is another reason to shut everything non-essential the hell down. It gives people time to do important work that could save lives. https://www.theatlantic.com/ideas/archive/2020/03/coronavirus-cancel-everything/607675/ https://www.theatlantic.com/ideas/archive/2020/03/coronaviru...

martyvis 7y ago

Don't researchers like this just go to WHO for support and assistance? This is a list of candidate vaccines. https://www.who.int/blueprint/priority-diseases/key-action/list-of-candidate-vaccines-developed-against-sars.pdf https://www.who.int/blueprint/priority-diseases/key-action/l...

iskander 7y ago

I just started working on the complementary side of the spike RBD-ACE2 interaction, making an aerosol of RBD peptide fragments to outcompete the virus for entry. This work is based on B-cell epitope mapping of SARS patients and subsequent identification of ACE2 binding peptides like: https://www.sciencedirect.com/science/article/pii/S0166354211005481 https://www.sciencedirect.com/science/article/pii/S016635421... I'm the "dry lab" side of this project -- looking for peptide candidates. My other collaborators at UNC are going to do formulate the aerosol and test for safety in mice. Normally this would be a very early stage in drug development, but it seems like we have to move quickly. So similar shout out to the Gates Foundation folks -- if you're interested in this approach email alex.rubinsteyn@unc.edu

bionhoward 7y ago

I’m not a doctor, but fusing a complement activator to a natural enzyme and megadosing it is a horrible idea because it’s gonna trigger complement activation in the context of a self protein, which could cause major autoimmunity, and ACE2 overload is gonna overactivate the angiotensin-aldosterone axis and deactivate renin via negative feedback, screw up your electrolytes which could cause arrhythmias, and give you high blood pressure. To avoid side effects, a therapy ought to be as orthogonal as possible to natural systems. A high dose of a hormone activator smushed together with an immune activator is definitely not orthogonal to natural systems. More useful to focus on genomic smart bombs like CRISPR Cas13 ( cough, https://github.com/bionicles/coronavirus https://github.com/bionicles/coronavirus ) or RNAi because they’re way, way, way, less likely to have side effects, they can last forever, can easily be retargeted to future germs hella quick, etc etc