THE VIABILITY OF NAFAMOSTAT IN TREATING SARS-CoV-2

ELSPETH TAMAR H. CAMPOMANES

BSN 1C Student

MARCK JASON TAGAPAN

Instructor

Biochemistry
CHY 47
MWF (9:00-10:00)

OCTOBER 2020
 THE VIABILITY OF NAFAMOSTAT IN TREATING SARS-CoV-2

At the end of 2019, a viral epidemic was recorded in Wuhan, China. (1) A couple

months later, it had become a worldwide pandemic that affected various sectors of

economies globally. Leaders, governments, and systems were extensively tested in order

to cope with the pandemic that is taking lives at an alarming rate. But this is not the first

time a pandemic has happened in the world.

Several pandemics has occurred in history, some more severe in death tolls than

now. The most similar to this was the 1918 Spanish flu, a strain of H1N1 virus. This virus

is most often termed as the deadliest pandemic in recent history as at the time it

occurred current medical and pharmaceutical technologies and advancements were not

yet discovered. And the Spanish flu was then mitigated by social distancing, isolation,

quarantine, good personal hygiene, use of disinfectants, and limited public gatherings.

(2)
All of which were applied unevenly. They did not have the guidelines and technologies

of today to lessen the death caused by the Spanish flu.

Currently these guidelines are at play in every country to mitigate its spread to

other people as the doctors and medical professionals work to create a vaccine. The

(3)
alarming spread of the COVID-19 virus across all parts of the world incapacitated

several industries and more people are losing jobs due the pandemic especially in the

travel sector. A cure or vaccine would mean that the world can go back to normal and

regain its losses.

The COVID -19 pandemic is also called the SARS-CoV-2 and is a part of a large

(4)
family of zoonotic viruses called coronavirus. SARS-CoV-2 is an abbreviation for

Severe Acute Respiratory Syndrome- CoronaVirus- 2 which indicates that this is the

(5)
second known kind of the virus. The SARS-CoV -2 can induce flu like symptoms which

causes severe respiratory infections that can cause death. It has a total incubation
period with a range of 1- 14 days and averaging 5-6 days and can spread while in its

(6)
incubation period.

The WHO states that several global studies are being conducted to help quickly

(7)
find its cure. There are many medications that are currently being researched as a

(8)
possible cure for SARS-CoV-2 one of which is Nafamostat mesylate.

Nafamostat mesylate or more commonly, Nafamostat, is an FDA approved drug

used as an anticoagulant which is a synthetic serine protease inhibitor and is used to

(9)(10)
treat pancreatitis. This drug was created in japan a few years prior and has

significant data on its safety in humans and is, therefore, tested and reliably safe for

(11)
human use and treatment. Nafamostat, according to the Drugbank is, “a fast-acting

proteolytic inhibitor used during hemodialysis to prevent the proteolysis of fibrinogen

(12)
into fibrin by competitively inhibiting several serine proteases including thrombin”.

This indicates that it functions to prevent coagulation (i.e. anticoagulant) in order to

mitigate various conditions wherein coagulation would be detrimental to recovery. It is a

small molecule, has a chemical formula of C19H17N5O2 and has what is considered to

(9)
be a short half-life making it necessary for continuous intravenous injection.

(13)
In Japan, Nafamostat is used in dialysis and sepsis treatment. Its use for

plasmin inhibition in treating fibrinolysis -related disorders was noted by Al-Horani and

(14)
Desai in 2014. Other uses for Nafamostat were also explored in terms of tumour

(15)
treatment and potential clinical applications by Chen and colleagues.

In the progression of the pandemic, new use of Nafamostat for the SARS-CoV-2

(10)
infection was noted by the University of Tokyo on March 18, 2020. In 2016 however,

the use of Nafamostat was also found to be effective against a similar virus, the MERS-

(16)
CoV infection. The similarity of MERS-CoV, SARS-CoV-2 and other coronaviruses is

that they are enveloped viruses which utilize an envelope protein to hijack the host cell

(17)
through membrane fusion. By suppressing a proteolysis, the transmembrane protease
 (6)(16)
serine 2 or TMPRSS2, successful hijacking of the cell by the virus was prevented.

Further research concerning the finding of its possible use for the current pandemic was

then conducted and tested if it holds true potential in comparison to other medications

that were able to mitigate similar viruses. The findings were able to support that

Nafamostat does indeed inhibit the activation of SARS-CoV -2 in comparison to other

medications of similar nature. By inhibiting the previously mentioned TMPRSS2 that is

(18)
needed in the membrane fusion prominent in most coronaviruses , the Nafamostat

was able to prove it use for the pandemic by exhibiting more potent effects than

(11)
previously utilized medication for the previous MERS-CoV. This result sparked more

research and clinical testing concerning its viability for mitigating infections caused by

SARS-CoV-2.

As of writing, there are several studies that look into Nafamostat as a cure for

SARS-CoV-2 and a scheduled clinical trial expected to be complete by mid and late 2021.

(19)(20)
Additionally, for Nafamostat, the many researches that are being published as of

writing in hopes to build on one another to establish its reliability and viability. Studies

concerning the use of Nafamostat against SARS-CoV-2 infections were conducted at

around mid-2020 and some still continue to this day. So far, laboratory testing of

Nafamostat is showing promising results against the SARS-CoV-2. A study which utilized

Nafamostat with favipiravir among 11 elderly people which are critically ill with the

SARS-CoV-2 infection found that this combination treatment was effective due to the

inhibition of mechanisms that make SARS-CoV-2 infections severe however due to the

small size of the study, more clinical trials in Japan are prompted to support and expand

(21)
on its findings.

A case reported by Jang and Rhee published in late May of 2020 indicated that

the use of Nafamostat for treatment on three elderly SARS-CoV-2 patients who need

oxygen therapy has helped in their recovery. The case noted a trend in these three
patients on how their conditions improved after the use of Nafamostat. The authors

prompted that their observations be further verified and evaluated in clinical trials since

(22)
the three cases were not randomized and of limited sample size.

Another study by Hoffman and colleagues, which utilized their previous work

about the possible use of Nafamostat and expanded on it found that due to SARS-CoV-

2’s similarity with SARS-CoV, Nafamostat was able to inhibit both viruses and further

proven Nafamostat as a viable medication for treatment. Furthermore, the study found

that SARS-CoV and SARS-CoV-2 indicates that it utilizes similar entry receptors, more

specifically, by binding to ACE-2 receptors suggesting a direction to take in antiviral

intervention. Additionally, in this paper they presented the mechanism that makes

nafamostat work against the SARS-CoV-2 indicating that due to the TMPRSS2 inhibiting

properties of Nafamostat, entry to the cell is then prevented prompting the clinical use

(23)
of Nafamostat in treating patients with SARS-CoV-2 infection in the current pandemic.

A study conducted by Yamamoto and colleagues in mid-2020 determined that

Nafamostat potently inhibits SARS-CoV-2’s hijacking of the cell by an S protein mediated

fusion and its viral infection in vitro. Additionally, the stated that Nafamostat is “the most

effective TMPRSS2 inhibitor” in current time. Additionally, the TMPRSS2 dependent

entry of the SARS-CoV-2 is what made Nafamostat so potent against compromising the

(16)(17)(18)(24)
virus’ activity.

As mentioned before, Nafamostat is only one of the many drugs being

(7)(8)
researched as a treatment for SARS-CoV-2 so a comparative analysis was conducted

by Ko and colleagues. In their study they distinguished 24 FDA approved drugs that

were being investigated as an antiviral medication. They compared the antiviral efficacy

by developing an antiviral screening assay to put each drug on equal grounds of

assessment and focused primarily on human lung cells for their assay. In it they found

that Nafamostat proved to be the most potent inhibitor of the SARS-CoV-2 infection
furthermore, the anticoagulant properties of Nafamostat was suggested to be also

beneficial in mitigating the blood clots associated with acute respiratory distress

(25)
syndrome which is a response associated with SARS-CoV-2 infections. However, they

also mentioned that it would be inconvenient to administer Nafamostat to a large group

(9)(25)
of patients since it needs to be continuously injected intravenously.

Treatments paired that include Nafamostat are also being evaluated so as to

enable quick recovery. The application of Nafamostat in the treatment for SARS-CoV-2 is

(26)
currently undergoing evaluation at the EUnetHTA. A combination therapy that pairs

(27)
Nafamostat with Heparin is currently being evaluated by doctors from Japan.

However, adverse effects of the use of Nafamostat was also noted and are also under

(28)
evaluation.

In summary, Nafamostat is a drug that holds weight and promise in treating

SARS-CoV-2 infections, as indicated by the studies aforementioned. However,

Nafamostat is not a cure-all drug and other medications are also needed to cover the full

extent of the virus in order to triumphantly eliminate SARS-CoV-2. Many efforts are

being done globally to mitigate the SARS-CoV-2 infection and the works of researchers

around the globe help in achieving this goal by doing their best to quickly deliver an

effective cure. As they are doing this, citizens and people of the Earth should also help

by following guidelines so as not to worsen the current circumstances and alleviate the

burden of the researchers and frontline workers.

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