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Nafamostat is expected to prevent the transmission of new coronavirus infection (COVID-19)

Nafamostat is expected to prevent the transmission of new coronavirus infection (COVID-19)

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Credit: Image: 2020 The University of Tokyo.

Nafamostat mesylate (brand name: Fusan), which is the drug used to treat acute pancreatitis, may effectively block the requisite viral entry process the new coronavirus (SARS-CoV-2) uses to spread and cause disease (COVID-19). The University of Tokyo announced these new findings on March 18, 2020.

According to the new research, Nafamostat can prevent the fusion of the envelope of the virus with host cell surface membranes, the first step in infection with the causative virus SARS-CoV-2. Nafamostat can inhibit the membrane fusion at a concentration less than one-tenth that of Camostat mesylate (brand name: Foypan), which was recently identified by a German group as an inhibitor of SARS-CoV-2 infection (Reference 1).

Both Nafamostat and Camostat were developed in Japan as treatments for pancreatitis and some other diseases. These drugs have been prescribed in Japan for many years and have adequate clinical data with regard to safety.

The University of Tokyo plans to launch clinical trials in April 2020 in order to evaluate the effectiveness of these two drugs for treating COVID-19.

Search for therapeutics from existing drugs that have been confirmed to be safe (drug repurposing) seems to be extremely worthwhile

Professor Jun-ichiro Inoue and Assistant Professor Mizuki Yamamoto of the Research Center for Asian Infectious Diseases of the Institute of Medical Science, the University of Tokyo, have identified Nafamostat as a strong candidate to fight COVID-19.

Even after the World Health Organization’s declaration of a pandemic, no drug has yet been shown to be effective for treating COVID-19 caused by the new coronavirus (SARS-CoV-2). The development of effective drugs is an urgent issue.

“Considering that SARS-CoV-2 infection is already spreading worldwide, drug repurposing (*1), which searches for therapeutics among existing drugs with established safety records, seems to be extremely worthwhile,” Inoue said.

The genomic RNA of coronaviruses such as SARS-CoV-2 is surrounded by an envelope composed of a lipid bilayer and envelope proteins. SARS-CoV-2 initiates human cell entry after the Spike protein (S protein) present on the envelope binds to a cell membrane receptor ACE2 (*2). The S protein is cleaved into S1 and S2 by a human cell-derived protease (proteolytic enzyme) that is assumed to be Furin. S1 then binds to its receptor, ACE2. The other fragment, S2, is cleaved by TMPRSS2 (*3), a human cell surface serine protease, resulting in membrane fusion. According to Hoffmann et al., ACE2 and TMPRSS2 are essential in airway cells for SARS-CoV-2 infection (Reference 1).

The research group already reported in 2016 that Nafamostat effectively inhibits MERS-CoV S protein-initiated membrane fusion. The researchers did this using the Dual Split Protein (DSP) reporter fusion assay (*4) to screen a library consisting of 1,017 FDA-approved drugs. This screening result, together with experimental data from MERS-CoV infection of cultured airway epithelial cell-derived Calu-3 cells (*5), led them to propose that Nafamostat could be effective at inhibiting MERS-CoV infection (Reference 2).

In the present study, they newly established a SARS-CoV-2 S protein-initiated fusion assay and found that in the concentration range from 10 to 1000 nM, Nafamostat suppressed SARS-CoV-2 S protein-initiated fusion utilizing 293FT cells (derived from human fetal kidney) (*6) ectopically expressing ACE2 and TMPRSS2. Then, a similar experiment was performed using Calu-3 cells, which are considered an appropriate model for the cells SARS-CoV infects in humans. Low concentrations in the 1-10 nM range of Nafamostat significantly suppressed membrane fusion. This is almost the same as the concentration range for inhibition of membrane fusion by the MERS-CoV S protein.

The research group also compared the effects of Nafamostat and Camostat. They found that Nafamostat inhibited SARS-CoV-2 S protein-initiated fusion at a concentration less than one-tenth that needed for Camostat. Based on the above explanation, they concluded that Nafamostat is the most effective drug against SARS-CoV-2 S protein-initiated fusion among the protease inhibitors used in clinical practice and tested so far.

Future potential of Nafamostat and Camostat

Nafamostat is administered clinically by intravenous infusion. The research group speculated that the blood concentration of Nafamostat after administration would exceed the concentration needed experimentally to inhibit membrane fusion via the SARS-CoV-2 S protein. Therefore, it is expected that Nafamostat will prevent SARS-CoV-2 from entering human cells. Camostat is an oral drug. Blood levels after oral administration may be inferior to Nafamostat.

“Both drugs could be used alone, or in combination with other antiviral drugs that target separate processes needed for virus production, such as RNA replication or viral protein processing,” said Inoue.

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Research Notes

(*1) drug repurposing: An attempt to find new effective uses for existing drugs whose safety in humans has already been adequately established in clinical practice.

(*2) ACE2: Angiotensin converting enzyme 2, which catalyzes the conversion of angiotensin II to angiotensin 1-7. ACE2 acts as a receptor for both SARS-CoV and SARS-CoV-2.

(*3) TMPRSS2: Transmembrane protease, serine 2. A serine protease present in the cell surface membrane. The SARS-CoV-2 coronavirus S protein is said to undergo proteolysis by TMPRSS2 after binding to the host receptor. Absent protein degradation, membrane fusion cannot proceed. Nafamostat is thought to inhibit S protein-initiated membrane fusion by inhibiting TMPRSS2 activity.

(*4) fusion assay system: A DSP (Dual Split Protein) reporter is used to detect fusion. DSP is a chimeric protein of split Renilla luciferase and split GFP (DSP1-7, DSP8-11), which has neither activity by itself, but can regain both GFP and luciferase activity upon self-association via its split GFP domain to a partner protein. By expressing these two proteins in separate cells, fusion between the cells can be quantified based on restored GFP and luciferase activity.

(*5) Calu-3 cells: Human bronchial epithelial cell-derived immortalized cells established from human lung cancer. It is used for functional analysis of respiratory cells. These cells are our appropriate model for the lung epithelial cells that SARS-CoV2 and MERS-CoV actually infect.

(*6) 293FT cell: an immortalized cell line derived from human fetal kidney. It has excellent properties such as fast cell growth and easy gene transfer.

References

1. Hoffmann et al. Cell 181, 1-10 (2020)
https://www.sciencedirect.com/science/article/pii/S0092867420302294?via%3Dihub

2. Yamamoto et al. Antimicrob Agents Chemother 60, 6532-6539 (2016)
https://aac.asm.org/content/60/11/6532

Media Contact
Jun-ichiro Inoue
jun-i@ims.u-tokyo.ac.jp

Original Source

https://www.ims.u-tokyo.ac.jp/imsut/en/about/press/page_00002.html

Related Journal Article

http://dx.doi.org/10.1016/j.cell.2020.02.052

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Comments on February Employment Report

The headline jobs number in the February employment report was above expectations; however, December and January payrolls were revised down by 167,000 combined.   The participation rate was unchanged, the employment population ratio decreased, and the …

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The headline jobs number in the February employment report was above expectations; however, December and January payrolls were revised down by 167,000 combined.   The participation rate was unchanged, the employment population ratio decreased, and the unemployment rate was increased to 3.9%.

Leisure and hospitality gained 58 thousand jobs in February.  At the beginning of the pandemic, in March and April of 2020, leisure and hospitality lost 8.2 million jobs, and are now down 17 thousand jobs since February 2020.  So, leisure and hospitality has now essentially added back all of the jobs lost in March and April 2020. 

Construction employment increased 23 thousand and is now 547 thousand above the pre-pandemic level. 

Manufacturing employment decreased 4 thousand jobs and is now 184 thousand above the pre-pandemic level.


Prime (25 to 54 Years Old) Participation

Since the overall participation rate is impacted by both cyclical (recession) and demographic (aging population, younger people staying in school) reasons, here is the employment-population ratio for the key working age group: 25 to 54 years old.

The 25 to 54 years old participation rate increased in February to 83.5% from 83.3% in January, and the 25 to 54 employment population ratio increased to 80.7% from 80.6% the previous month.

Both are above pre-pandemic levels.

Average Hourly Wages

WagesThe graph shows the nominal year-over-year change in "Average Hourly Earnings" for all private employees from the Current Employment Statistics (CES).  

There was a huge increase at the beginning of the pandemic as lower paid employees were let go, and then the pandemic related spike reversed a year later.

Wage growth has trended down after peaking at 5.9% YoY in March 2022 and was at 4.3% YoY in February.   

Part Time for Economic Reasons

Part Time WorkersFrom the BLS report:
"The number of people employed part time for economic reasons, at 4.4 million, changed little in February. These individuals, who would have preferred full-time employment, were working part time because their hours had been reduced or they were unable to find full-time jobs."
The number of persons working part time for economic reasons decreased in February to 4.36 million from 4.42 million in February. This is slightly above pre-pandemic levels.

These workers are included in the alternate measure of labor underutilization (U-6) that increased to 7.3% from 7.2% in the previous month. This is down from the record high in April 2020 of 23.0% and up from the lowest level on record (seasonally adjusted) in December 2022 (6.5%). (This series started in 1994). This measure is above the 7.0% level in February 2020 (pre-pandemic).

Unemployed over 26 Weeks

Unemployed Over 26 WeeksThis graph shows the number of workers unemployed for 27 weeks or more.

According to the BLS, there are 1.203 million workers who have been unemployed for more than 26 weeks and still want a job, down from 1.277 million the previous month.

This is down from post-pandemic high of 4.174 million, and up from the recent low of 1.050 million.

This is close to pre-pandemic levels.

Job Streak

Through February 2024, the employment report indicated positive job growth for 38 consecutive months, putting the current streak in 5th place of the longest job streaks in US history (since 1939).

Headline Jobs, Top 10 Streaks
Year EndedStreak, Months
12019100
2199048
3200746
4197945
52024138
6 tie194333
6 tie198633
6 tie200033
9196729
10199525
1Currrent Streak

Summary:

The headline monthly jobs number was above consensus expectations; however, December and January payrolls were revised down by 167,000 combined.  The participation rate was unchanged, the employment population ratio decreased, and the unemployment rate was increased to 3.9%.  Another solid report.

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Immune cells can adapt to invading pathogens, deciding whether to fight now or prepare for the next battle

When faced with a threat, T cells have the decision-making flexibility to both clear out the pathogen now and ready themselves for a future encounter.

Understanding the flexibility of T cell memory can lead to improved vaccines and immunotherapies. Juan Gaertner/Science Photo Library via Getty Images

How does your immune system decide between fighting invading pathogens now or preparing to fight them in the future? Turns out, it can change its mind.

Every person has 10 million to 100 million unique T cells that have a critical job in the immune system: patrolling the body for invading pathogens or cancerous cells to eliminate. Each of these T cells has a unique receptor that allows it to recognize foreign proteins on the surface of infected or cancerous cells. When the right T cell encounters the right protein, it rapidly forms many copies of itself to destroy the offending pathogen.

Diagram depicting a helper T cell differentiating into either a memory T cell or an effector T cell after exposure to an antigen
T cells can differentiate into different subtypes of cells after coming into contact with an antigen. Anatomy & Physiology/SBCCOE, CC BY-NC-SA

Importantly, this process of proliferation gives rise to both short-lived effector T cells that shut down the immediate pathogen attack and long-lived memory T cells that provide protection against future attacks. But how do T cells decide whether to form cells that kill pathogens now or protect against future infections?

We are a team of bioengineers studying how immune cells mature. In our recently published research, we found that having multiple pathways to decide whether to kill pathogens now or prepare for future invaders boosts the immune system’s ability to effectively respond to different types of challenges.

Fight or remember?

To understand when and how T cells decide to become effector cells that kill pathogens or memory cells that prepare for future infections, we took movies of T cells dividing in response to a stimulus mimicking an encounter with a pathogen.

Specifically, we tracked the activity of a gene called T cell factor 1, or TCF1. This gene is essential for the longevity of memory cells. We found that stochastic, or probabilistic, silencing of the TCF1 gene when cells confront invading pathogens and inflammation drives an early decision between whether T cells become effector or memory cells. Exposure to higher levels of pathogens or inflammation increases the probability of forming effector cells.

Surprisingly, though, we found that some effector cells that had turned off TCF1 early on were able to turn it back on after clearing the pathogen, later becoming memory cells.

Through mathematical modeling, we determined that this flexibility in decision making among memory T cells is critical to generating the right number of cells that respond immediately and cells that prepare for the future, appropriate to the severity of the infection.

Understanding immune memory

The proper formation of persistent, long-lived T cell memory is critical to a person’s ability to fend off diseases ranging from the common cold to COVID-19 to cancer.

From a social and cognitive science perspective, flexibility allows people to adapt and respond optimally to uncertain and dynamic environments. Similarly, for immune cells responding to a pathogen, flexibility in decision making around whether to become memory cells may enable greater responsiveness to an evolving immune challenge.

Memory cells can be subclassified into different types with distinct features and roles in protective immunity. It’s possible that the pathway where memory cells diverge from effector cells early on and the pathway where memory cells form from effector cells later on give rise to particular subtypes of memory cells.

Our study focuses on T cell memory in the context of acute infections the immune system can successfully clear in days, such as cold, the flu or food poisoning. In contrast, chronic conditions such as HIV and cancer require persistent immune responses; long-lived, memory-like cells are critical for this persistence. Our team is investigating whether flexible memory decision making also applies to chronic conditions and whether we can leverage that flexibility to improve cancer immunotherapy.

Resolving uncertainty surrounding how and when memory cells form could help improve vaccine design and therapies that boost the immune system’s ability to provide long-term protection against diverse infectious diseases.

Kathleen Abadie was funded by a NSF (National Science Foundation) Graduate Research Fellowships. She performed this research in affiliation with the University of Washington Department of Bioengineering.

Elisa Clark performed her research in affiliation with the University of Washington (UW) Department of Bioengineering and was funded by a National Science Foundation Graduate Research Fellowship (NSF-GRFP) and by a predoctoral fellowship through the UW Institute for Stem Cell and Regenerative Medicine (ISCRM).

Hao Yuan Kueh receives funding from the National Institutes of Health.

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Stock indexes are breaking records and crossing milestones – making many investors feel wealthier

The S&P 500 topped 5,000 on Feb. 9, 2024, for the first time. The Dow Jones Industrial Average will probably hit a new big round number soon t…

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Major stock indexes were hitting or nearing records in February 2024, as they were in early 2020 when this TV chyron appeared. AP Photo/Richard Drew

The S&P 500 stock index topped 5,000 for the first time on Feb. 9, 2024, exciting some investors and garnering a flurry of media coverage. The Conversation asked Alexander Kurov, a financial markets scholar, to explain what stock indexes are and to say whether this kind of milestone is a big deal or not.

What are stock indexes?

Stock indexes measure the performance of a group of stocks. When prices rise or fall overall for the shares of those companies, so do stock indexes. The number of stocks in those baskets varies, as does the system for how this mix of shares gets updated.

The Dow Jones Industrial Average, also known as the Dow, includes shares in the 30 U.S. companies with the largest market capitalization – meaning the total value of all the stock belonging to shareholders. That list currently spans companies from Apple to Walt Disney Co.

The S&P 500 tracks shares in 500 of the largest U.S. publicly traded companies.

The Nasdaq composite tracks performance of more than 2,500 stocks listed on the Nasdaq stock exchange.

The DJIA, launched on May 26, 1896, is the oldest of these three popular indexes, and it was one of the first established.

Two enterprising journalists, Charles H. Dow and Edward Jones, had created a different index tied to the railroad industry a dozen years earlier. Most of the 12 stocks the DJIA originally included wouldn’t ring many bells today, such as Chicago Gas and National Lead. But one company that only got booted in 2018 had stayed on the list for 120 years: General Electric.

The S&P 500 index was introduced in 1957 because many investors wanted an option that was more representative of the overall U.S. stock market. The Nasdaq composite was launched in 1971.

You can buy shares in an index fund that mirrors a particular index. This approach can diversify your investments and make them less prone to big losses.

Index funds, which have only existed since Vanguard Group founder John Bogle launched the first one in 1976, now hold trillions of dollars .

Why are there so many?

There are hundreds of stock indexes in the world, but only about 50 major ones.

Most of them, including the Nasdaq composite and the S&P 500, are value-weighted. That means stocks with larger market values account for a larger share of the index’s performance.

In addition to these broad-based indexes, there are many less prominent ones. Many of those emphasize a niche by tracking stocks of companies in specific industries like energy or finance.

Do these milestones matter?

Stock prices move constantly in response to corporate, economic and political news, as well as changes in investor psychology. Because company profits will typically grow gradually over time, the market usually fluctuates in the short term, while increasing in value over the long term.

The DJIA first reached 1,000 in November 1972, and it crossed the 10,000 mark on March 29, 1999. On Jan. 22, 2024, it surpassed 38,000 for the first time. Investors and the media will treat the new record set when it gets to another round number – 40,000 – as a milestone.

The S&P 500 index had never hit 5,000 before. But it had already been breaking records for several weeks.

Because there’s a lot of randomness in financial markets, the significance of round-number milestones is mostly psychological. There is no evidence they portend any further gains.

For example, the Nasdaq composite first hit 5,000 on March 10, 2000, at the end of the dot-com bubble.

The index then plunged by almost 80% by October 2002. It took 15 years – until March 3, 2015 – for it return to 5,000.

By mid-February 2024, the Nasdaq composite was nearing its prior record high of 16,057 set on Nov. 19, 2021.

Index milestones matter to the extent they pique investors’ attention and boost market sentiment.

Investors afflicted with a fear of missing out may then invest more in stocks, pushing stock prices to new highs. Chasing after stock trends may destabilize markets by moving prices away from their underlying values.

When a stock index passes a new milestone, investors become more aware of their growing portfolios. Feeling richer can lead them to spend more.

This is called the wealth effect. Many economists believe that the consumption boost that arises in response to a buoyant stock market can make the economy stronger.

Is there a best stock index to follow?

Not really. They all measure somewhat different things and have their own quirks.

For example, the S&P 500 tracks many different industries. However, because it is value-weighted, it’s heavily influenced by only seven stocks with very large market values.

Known as the “Magnificent Seven,” shares in Amazon, Apple, Alphabet, Meta, Microsoft, Nvidia and Tesla now account for over one-fourth of the S&P 500’s value. Nearly all are in the tech sector, and they played a big role in pushing the S&P across the 5,000 mark.

This makes the index more concentrated on a single sector than it appears.

But if you check out several stock indexes rather than just one, you’ll get a good sense of how the market is doing. If they’re all rising quickly or breaking records, that’s a clear sign that the market as a whole is gaining.

Sometimes the smartest thing is to not pay too much attention to any of them.

For example, after hitting record highs on Feb. 19, 2020, the S&P 500 plunged by 34% in just 23 trading days due to concerns about what COVID-19 would do to the economy. But the market rebounded, with stock indexes hitting new milestones and notching new highs by the end of that year.

Panicking in response to short-term market swings would have made investors more likely to sell off their investments in too big a hurry – a move they might have later regretted. This is why I believe advice from the immensely successful investor and fan of stock index funds Warren Buffett is worth heeding.

Buffett, whose stock-selecting prowess has made him one of the world’s 10 richest people, likes to say “Don’t watch the market closely.”

If you’re reading this because stock prices are falling and you’re wondering if you should be worried about that, consider something else Buffett has said: “The light can at any time go from green to red without pausing at yellow.”

And the opposite is true as well.

Alexander Kurov does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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