[philipn]

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. 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/ see "ACE2 immunoadhesin strategy"

[sandGorgon]

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]

You should feel proud. Thanks!

[iskander]

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/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 [e-mail]

[davidw]

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/coronaviru...

[pkaye]

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

[delhanty]

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

[philipn]

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

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.

[dpratt71]

I'm fairly out of my depth here, but it's somewhat relevant to my personal situation:

When this came up for discussion on HN a few days ago, I was initially confused, as some of what I read seemed to suggest that taking e.g. lisinopril could possibly increase the risk of an infection because it seems to increase the expression of ACE2 receptors that are used by the virus to infect cells.

On the other hand, some of what I read seemed to suggest that ACE inhibitors (e.g. lisinopril) could have a therapeutic benefit. The virus is going to inactivate a bunch of ACE2 receptors through the course of infection. Since ACE2 receptors inactivate angiotensin, that would leave a lot of active angiotensin floating around, which is potentially very bad. ACE inhibitors would seem to help here because they inhibit the active form of angiotensin from being created in the first place.

Now I'm wondering: Is it possible that taking lisinopril could increase the risk of serious infection for those of us not yet infected, but also could reduce the severity of an active infection?

[frankbeerstein]

I agree. There is a +6% increase in COVID-19 mortality for those with hypertension. Assume all were on BP meds. They're cheap, & doctors usually insist. If ACEs or ARBs were protective, it should be more like -6%. Right? Losartan = 400% more ACE2, Lisinopril = 100% more ACE2.

Elderly people are usually on BP meds. Diabetics are frequently prescribed Losartan to protect their kidneys. I know. I am a diabetic, and was prescribed it for that reason and also for high BP.

As a diabetic over 50 with high BP I have a greater interest than most. Especially since my wife was exposed to coronavirus, is sick, and I am starting to feel unwell.

Stopped taking losartan yesterday. Have some tenofovir lying around and might start taking it. It's the only antiviral I was able to get my hands on. Hopefully my chloroquine arrives in the mail soon.

[Bach-4ever]

I read a paper that suggested caffeic acid was the anti-viral component of elderberry extract that was actually inhibiting HCoV-NL63 viral attachment and infection of human lung cells in vitro (Virus Research, 273 (2019)197767). This paper speculated that caffeic acid binds to ACE2 and inhibits viral attachment and infection via this route. Another paper suggested 95% absorption in humans dosed with 500 mg in 200 mL of hot water. A third paper that looked at 2-year study in SD rats suggested pro-carcinogenic properties, but many other papers suggest anti-oxidant/anti-inflammatory/anti-carcinogenic properties. If I start to come down with it, I think I'm going to do a 500 mg caffeic acid dose.

[hef19898]

I am propably among the most ardent critics of twitter and social media when it comes to Corona. And then comes a guy like you. Stuff like that should be among every top comment, everywhere when it comes to this. Along side the WHO situation reports and guidelines. So, thank you!

[christoph]

Could you possibly comment on this, as it strikes me as odd, regarding the surprising characteristics of smokers from this study from China:

https://www.nejm.org/doi/full/10.1056/NEJMoa2002032

86.9% of non severe cases had never smoked 77.9% of severe cases had never smoked

Contrasted with 1.3% and 5.2% in former smokers and 11.8% and 16.9% in current smokers.

[philipn]

I think the table in that paper is just confusing. The parenthesized numbers are for portion of the total number of people, rather than the portion of that category.

For instance, there are 137 current smokers. 108 are listed as non-severe. 29 are listed as severe. This means 108/137 = 79% non-severe, 29/137 21% severe.

Never smoked: 927 total, 793/927 non-severe (86%), 134/927 severe (14%).

Hope that makes sense. That table confused me too. Don't start smoking!

[Alex3917]

For context, around 60% of men in China smoke. Your proximate interpretation of the numbers is correct, but I think the real question is where are there so few smokers in the data. (And whether smoking confers some sort of protective effect by upregulating ACE2 receptors.)

[Alex3917]

A few days ago I started taking a low dose of an OTC ACE inhibitor in order to upregulate my ACE2 receptors. This is what the literature that was written before the current epidemic about surviving novel Coronavirus pandemics says to do, and the new evidence that comes out each day is actually validating this strategy.

It's only the scientists who didn't start studying Coronaviruses until two weeks ago who seem to think that having ACE2 receptors is dangerous.

[refurb]

If the virus is infecting a cell through the ACE2 receptor, wouldn’t upregulating the receptor just increase the risk of infection?

As per the paper, you want to either block the receptor or down regulate it.

[Alex3917]

That definitely could be true, but from what I've read it probably isn't. One of the ways the virus kills people is by destroying their ACE2 receptors, which your lung cells need to function. If you blocked them all, your lung cells would die anyway. So as long as the virus can enter your lung cells, you might as well prevent it from killing them by making extra ACE2 receptors. That's the theory anyway.

There are also many other ways you can block the virus from entering your lungs that don't involve downregulating your ACE2 receptors.

[webmobdev]

Asking as a lay man, are you taking this as a preventive measure?

[Alex3917]

Yes. My risk of death is supposedly nominal, but I want to avoid any lung damage.

I'm taking a low dose though, in part to hedge my bets, and in part because I don't want to bleed out if I get into a bike accident.

[dboreham]

>OTC ACE inhibitor

Which country are you in?

[Alex3917]

USA.

[yumraj]

Could someone explain this in laymen terms please.

[fxtentacle]

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-v...

[philipn]

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__

[forkexec]

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]

So would there be an additional risks from coronavirus to those taking ACE or ARB inhibitors?

[ignoramous]

See a recent albeit heated discussion here: https://news.ycombinator.com/item?id=22500063

[wbl]

ACE is the enzyme that ACE inhibitors inhibit. Why is it expressed in the lungs? I have no clue.

[epmaybe]

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]

But why the lungs and not the liver?

[epmaybe]

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.

[dreamcompiler]

IIRC, conventional ACE inhibitors don't inhibit ACE2, which would be be needed to fight COVID-19.

[jokowueu]

Your are correct It's related to ACE inhibitors .

[dharma1]

edit: looks like it is. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029759/#ref-60

Is this the soluble ACE2 mentioned?

https://www.clinicaltrialsarena.com/news/ubc-apeiron-biologi...

https://pipelinereview.com/index.php/2020022673884/Proteins-...

https://connect.myesr.org/course/novel-coronavirus-outbreak-...

It was initially discovered and developed during the SARS epidemic - https://www.nature.com/articles/nm1267

[bionhoward]

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 ) 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

[jokowueu]

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

[philipn]

List of repurposed drugs (not comprehensive) 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/co...

[martyvis]

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/l...

[jacobush]

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

[onion2k]

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]

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]

I mean, I get where you are coming from but it still is a huge stretch to make a blanket statement like that.