
SARSCoV2 cell entry depends on ACE2 and TMPRSS2, blockable by protease inhibitor - ignoramous
https://www.cell.com/cell/fulltext/S0092-8674(20)30229-4
======
jamesblonde
A few medicines of note here: Ace inhibitors are a well known treatment that
reduces blood pressure.

However, there are two different types of medicine undergoing clinical trials:
Lopinavir/Ritonavir (tradename KALETRA) - a HIV medicine has shown promise and
chloroquine - a 60+ year old anti-malaria medicine

Personally, i ordered chloroquine - well known safety profile. I won't wait
for docs to discuss prescribing it if i get any symptoms. I may even take it
for preventative use. I also have sequenced my DNA (full genome), and checked
if I have any mutations that are know to increase production of ACE2 -
increasing susceptibility to acquiring covid-19:

[https://www.nature.com/articles/s41421-020-0147-1](https://www.nature.com/articles/s41421-020-0147-1)

~~~
nkrumm
Everyone is welcome to take their own health into their own hands. However,
for others looking to this as advice, please be aware that:

1) ACE inhibitors (lisinopril, etc.) are generally though to be enzymatic
inhibitors of ACE, not ACE2 [1]. Also, enzymatic inhibition of the enzyme does
not mean that it will prevent a virus from using that protein as an entry
mechanism.

2) Chloroquine is an old drug with a well known safety profile, but it is
certainly not a "safe" drug-- there are many known side effects including life
threatening or severely disabling ones. As an MD, I recommend always
consulting with your own medical provider(s) before starting any medications.

[1] e.g.,
[https://www.ncbi.nlm.nih.gov/pubmed/15897343](https://www.ncbi.nlm.nih.gov/pubmed/15897343)

~~~
a_imho
_Everyone is welcome to take their own health into their own hands._

Since when? Last time I checked my body my choice does not apply to the vast
majority of pharmaceuticals unless a third party approves it.

~~~
Certhas
It is illegal to take them? Or are you merely referring to the fact that it's
illegal to sell them?

~~~
Kaze404
Since that's the only legal way of acquiring them, yes.

------
DataDrivenMD
Consider me skeptical of the practical significance of their findings. IMO,
protease inhibitors are a moot point if the they don't also block cell entry
via antibody-dependent enhancement (ADE):

\- [http://viruseradication.com/abstract-
details.php?abstract_id...](http://viruseradication.com/abstract-
details.php?abstract_id=645)

\-
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178114/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178114/)

\-
[https://jvi.asm.org/content/94/5/e02015-19.abstract](https://jvi.asm.org/content/94/5/e02015-19.abstract)

It's been a while since my vaccine research days at the NIH, so take my
skepticism with a grain of salt.

~~~
snapetom
ADE has me worried the most. There's some circumstantial evidence that
COVID-19 might use ADE. The arguments against it (from claimed medical
experts) on reddit was basically "ADE is extremely rare."

If the evidence for/against something is based solely on percentages, you'll
get a raised eyebrow from me.

~~~
l33tman
In medicine and biology, evidence IS based on percentages. That's why all
these papers that present possible mechanisms with no numbers to back them up
are confusing people. You need thousands to hundreds of thousands of
datapoints. This is not an exact engineering discipline (yet..) unfortunately.

~~~
rscho
A minor counterpoint from a clinical researcher: in medicine and biology,
evidence is mostly based on bullshit, not percentages.

------
forkexec
Million-dollar question:

what kind of cellular dysfunction would be caused by blockading ACE2 and
TMPRSS2?

~~~
forkexec
_ACE2 has direct effects on cardiac functiona and is expressed predominantly
in vascular endothelial cells of the heart and the kidneys._ -wikipedia

 _ACE2 entry is [betacoronavirus] lineage B clade 1 specific._

\----- TMPRSS2 -----

• positive regulation of viral entry into host cell

• protein autoprocessing

• receptor-mediated endocytosis

• proteolysis

• vesicle-mediated transport

• endocytosis

 _This gene was demonstrated to be up-regulated by androgenic hormones in
prostate cancer cells and down-regulated in androgen-independent prostate
cancer tissue. The protease domain of this protein is thought to be cleaved
and secreted into cell media after autocleavage. The biological function of
this gene is unknown._ \- wikipedia

Interestingly, TMPRSS2 is the same exact pathway used by SARS, murine
respirovirus and influenza. So, a blockade or modification of this might be a
way to cure the flu as well.

TMPRSS2 entry is found in betacoronavirus lineage B, but not specific to it.

------
KaiserPro
[https://www.nature.com/articles/d41587-020-00003-1](https://www.nature.com/articles/d41587-020-00003-1)
has a roundup of other drugs that are currently on trail. From said article,
we can expect data in april.

------
bittersourspicy
camostat mesylate + E-64d

Camostat

CAS: 59721-29-8

Approvals: Japan

$0.10/mg in bulk (2 week lead time), or $1.25/mg in-stock

[https://en.wikipedia.org/wiki/Camostat](https://en.wikipedia.org/wiki/Camostat)

[https://www.adooq.com/camostat-mesylate.html](https://www.adooq.com/camostat-
mesylate.html)

[https://www.medkoo.com/products/11665](https://www.medkoo.com/products/11665)

\----------

E-64d

CAS: 88321-09-9

LD50 in rats: >100000 mg/kg

$12.5/mg in-stock

[https://www.sigmaaldrich.com/catalog/product/sigma/e8640](https://www.sigmaaldrich.com/catalog/product/sigma/e8640)

[https://www.apexbt.com/e-64d.html](https://www.apexbt.com/e-64d.html)

\----------

Obviously: untested, unknown dosage and not FDA approved. It would need a
little DMSO to dissolve both.

~~~
lm28469
Yes, definitely self medicate with untested drugs for what basically is the
flu as long as you're under 60 years old, what could possibly go wrong ...

~~~
missosoup
At a lower bound estimate of 30-60x the case fatality rate of flu and some
unexplained reinfection mechanism, 'it's just the flu bro' is getting really
disingenuous.

A simple way to explain this to simple minded people is: ever heard of
international travel and massive sports events being cancelled, and armies
getting mobilised because of just the flu? No? That's because that's not what
this is.

Poster made it clear that the drug is untested an experimental, but ultimately
each individual is responsible for their own wellbeing and should be aware of
last-ditch options if things get dire.

~~~
lm28469
> 30-60x the case fatality

Under 60 years old, certainly not.

> some unexplained reinfection mechanism

unexplained and more importantly totally unproven.

It certainly is more dangerous than the flu but if you're not weak or old
taking some random untested drugs recommended on an internet forum by someone
who has no idea what he's talking about is most likely more risky than just
following health organisations recommendations.

~~~
missosoup
> unexplained and more importantly totally unproven.

What do you mean unproven? There are reinfection cases with incredibly low
latencies being reported all over the globe. A handful of reports might be
written off as misunderstandings or outliers but there are multiple reports
per day from reputable sources. Reinfection is certainly a factor, the only
question is by what mechanism.

[https://www.scmp.com/news/china/society/article/3048320/chin...](https://www.scmp.com/news/china/society/article/3048320/china-
coronavirus-deadly-day-hubei-record-high-42-patients-die)

[https://twitter.com/OH_mes2/status/1233346594428186627](https://twitter.com/OH_mes2/status/1233346594428186627)

> weak or old

Does a 29 year old healthy male sound weak or old?

[https://twitter.com/lilkuo/status/1230699297508745217](https://twitter.com/lilkuo/status/1230699297508745217)

> just following health organisations recommendations

You mean like the CDC which is being actively dismantled while the president
of the US goes on national TV and calls their messaging fake news?

The health of every individual is ultimately in their own hands. Being
informed of everything pertinent to their health including experimental last-
ditch treatments is in everyone's interest. Don't look to authorities to
babysit you through a pandemic, especially not in poor countries or USA. By
hitting the downvote button on the grandparent comment, you're electing to
censor it in some sort of misguided do-gooding effort, inspite of HN
guidelines.

~~~
xorfish
A false negative doesn't make a reinfection.

There are going to be a lot of still positive people that test negative with a
test that has a high enough false negative rate.

~~~
missosoup
Patients only get retested after they appear to have recovered. That means
their symptoms have subsided.

You can get super pedantic with semantics and call it a false negative, which
might be technically true if the virus subsides but has the ability to persist
- which is one of the potential mechanisms for reinfection, but has not been
confirmed.

But none of that changes the fact that people are getting reinfected and
sometimes dropping dead after appearing to have recovered by all measures.
This is clearly different to 'it's just the flu bro'.

