Study discovers inhibition of SARS-CoV-2 entry priming protein by approved drug

The COVID-19 pandemic caused by the severe acute respiratory syndrome -coronavirus 2 (SARS-CoV-2) has spread to most of the world, causing millions of cases and hundreds of thousands of deaths. A new study published on the preprint server bioRxiv* shows that a protease inhibitor drug already approved by the Food and Drug Administration (FDA) could inhibit viral entry.

What is TMPRSS2?

The SARS-CoV-2 enters the host cell via the angiotensin-converting enzyme 2 (ACE2) receptor, to which it attaches via the spike (S) protein on the virus envelope. Another host protein called transmembrane protein serine protease TMPRSS2 also plays a vital role in processing the S protein and receptor. This is necessary for further interaction of the S protein and ACE2 receptor leading to infection.

When the TMPRSS2 protein is blocked by a molecule called camostat mesylate, the virus cannot enter the host cell. This offers a promising avenue for the therapy of this infection.

TMPRSS2 plays a role in several coronavirus infections, such as the earlier SARS, MERS and the current SARS-CoV-2, and also some influenza infections. It is also important biologically as a prostate cancer oncogene.

It is a promising antiviral drug target because it is a host protein. Drugs that are designed to fit viral proteins are always subject to the risk of becoming obsolete due to the high rate of viral genomic mutations that can change the protein characteristics. However, agents that are directed against host proteins are less likely to counter rapid drug resistance.

This type of drug does carry one risk, however. This is the risk that alterations in the protein pathway involved will also cause undesirable changes in the host physiology.

Researchers have been concerned that TMPRSS2 is the starting point for a series of amplifying proteolytic activation events. These are important in regulating seminal fluid and lung proteins since TMPRSS2 is a sodium channel regulator.

However, mouse experiments in which the mice lack this protein do not show any apparent deficits. Scientists hope that this means other proteases can replace the protein with respect to its function.
This could mean it is safe to target TMPRSS2 during viral infections. Moreover, there are already approved drugs that act to inhibit the proteolytic activity of this enzyme, such as camostat mesylate, nafamostat, and BHH.

How was the study done?

The researchers did a functional screening to find TMPRSS2 inhibitors and compared their efficiency. The tested molecules include secretory leukocyte peptidase inhibitor (SLPI), 4-(2-aminomethyl) benzenesulfonyl fluoride (AEBSF), Boc-Gln-Ala-Arg-7-Amino-4-methylcoumarin (BOC-QAR-AMC), camostat mesylate, bromhexine hydrochloride (BHH) and alpha 1 antitrypsin (A1AT).

They used a human cell line in which TMPRSS2 was expressed at very high levels, at 2.5 times that of control cells. The rate of proteolysis was increased over 3.5 fold compared to that of controls and remained more than double after hours.

What did the study show?

The researchers used camostat mesylate, a known TMPRSS2 inhibitor, in control cells. At concentrations as low as 100 nM, it showed inhibitory action.

Next, they tested for the inhibitory action of SLPI, at various concentrations, without success. However, A1AT showed dose-dependent inhibition of the proteolysis induced by TMPRSS2 with the highest effects at a concentration of 1 μM.

With AEBSF, a protease inhibitor capable of inhibiting influenza infection in a murine experiment, dose-dependent inhibition of TMPRSS2 occurred with a peak at 1 μM.

BHH is an FDA-approved drug used as a mucolytic and cough suppressant, which inhibits TMPRSS2 in a dose-dependent manner, but is less efficient than A1AT or AEBSF.

What do the findings imply?

In the current study, the researchers shortlisted two novel inhibitor molecules, namely, AEBSF and A1AT. It is possible that these inhibitors could potentially block viral activity by preventing TMPRSS2’s action on S protein processing.

A1AT is a small protein manufactured in the liver and present in the blood at high levels. It can shoot up six times in acute inflammation or injury. It is delivered to many organs when administered as a drug.

In the lungs, it blocks the action of the protease enzymes neutrophil elastase, proteinase 3, and cathepsin G. it also enhances the clearance of apoptotic cells, and so protects the body against tissue damage and overactive inflammation.

Mutations in the A1AT gene could lead to subnormal levels of the protein, causing the lung to suffer protein breakdown and widespread emphysema of the lobes. The FDA approved the use of A1AT as a replacement in cases of deficiency.

While A1AT was previously known to block H3N2 infection and influenza B virus in animal models, this is the first time that it is being shown to inhibit TMPRSS2. The earlier viruses do not need to be primed by TMPRSS2, and their blocking was presumed to be via hepsin inhibition.

The use of A1AT may reduce the disease severity in COVID-19 by dampening inflammation within the alveoli as well as inhibiting TMPRSS2. Earlier experiments have shown that the levels of truncated A1AT found in peripheral blood in SARS patients are higher than in controls, and rise in proportion to disease severity. This could mean that this protein is a component of a natural immune response against CoV infection as well as acute lung disease.

A1AT is a serine protease inhibitor (SERPIN) and thus has a reactive center loop that is broken apart by interaction with proteases. This breakage causes A1AT to undergo a conformational change, which results in irreversible covalent bonding with the target protease, inhibiting its activity permanently.

It is thought that the truncated A1AT seen in SARS patients arise from this type of cleavage caused by TMPRSS2 and other proteases.

AEBSF also blocks the activity of TMPRSS2, being a small molecule that inhibits proteases nonspecifically. It has caused a decrease in the levels of both H1N1 and H7N7 nuclear proteins within the lung tissue of mice infected with influenza. Its mechanism of action is via a covalent bonding, which adds a sulfonyl group to the active site.

The use of protease inhibitors – camostat mesylate, A1AT, BHH, and AEBSF – could help develop antivirals against COVID-19. The researchers say, “A1AT may be particularly effective as it has the dual capacity, inhibiting TMPRSS2 (and hence viral uptake and subsequent replication) and possessing anti-inflammatory activity. The ready availability of A1AT calls attention to its potential clinical use for the COVID-19 pandemic.”

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Can one shot keep alcoholics off alcohol?

The key to becoming a teetotaller might be a one-off shot of a different drug. Scientists say that a new treatment involving a shot of ketamine could help heavy drinkers substantially reduce alcohol consumption.

Ketamine, more commonly used as an anaesthetic and in animal tranquilisers, also finds popularity as a recreational drug. Now, scientists say that it can be used to "rewrite" drink-related memories, reports The Guardian. Possibly, in the future, this discovery could be developed into a new form of treatment for alcohol addiction.

The trial was led by a psychologist. The  Dr. says, "There was a really big drop-off, which was maintained or got even better up to nine months. I was surprised by how effective it was.”

According to the news, a growing body of evidence suggests that ketamine can be used to disrupt memories. Adapting that to addiction, the memories that drive harmful patterns of behaviour, researchers believe, can be influenced by ketamine. Thus, harmful habits and unhelpful memories can potentially be unlearned.

The study was conducted with 90 people who indulged in hazardous levels of drinking, but did not have a formal diagnosis of alcohol use disorder. They were drinking roughly 30 pints of beer per week. 

On the first day the participants were given a glass of beer that they were allowed to drink after viewing some images of beer and people drinking. 

The next day, while the same was promised, the beer was however taken away at the end.
Unexpected removal of an anticipated reward can temporarily disrupt learned associations. With ketamine however a brain receptor called NMDA can be blocked. This is necessary for the formation of memories.

Once the beer was taken away, a third of the participants were given an intravenous ketamine infusion, while others were given a placebo infusion. The third group got ketamine without a psychological intervention.

The researchers, over a 10-day follow up noted that people given ketamine along with psychological intervention showed significant reductions in their urge to drink as compared to the other participants.
The effect was sustained over a nine-month follow-up and it was noted that all three groups had reduced their drinking. Those given the ketamine therapy had a much more pronounced overall improvement

The research team now intends to apply for funding to carry out a clinical trial.

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Previously unknown pain-sensing organ discovered in human body

Swedish researchers have discovered a new sensory organ in the skin that is sensitive to painful mechanical damage such as pricks and pressure.

The new pain-sensitive organ is organised together with pain-sensitive nerves in the skin, says researchers.

"Our study shows that sensitivity to pain does not occur only in the skin's nerve fibres, but also in this recently-discovered pain-sensitive organ," said a professor.

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"The discovery changes our understanding of the cellular mechanisms of physical sensation and it may be of significance in the understanding of chronic pain," the Prof. said. 

In experiments, the researchers also blocked the organ and saw a resultant decreased ability to feel mechanical pain.

Almost one person in every five experiences constant pain and there is a considerable need to find new painkilling drugs, according to research published. The discovery of the previously unknown pain-sensing organ could lead to the development of new painkilling drugs.

The team found that these Schwann cells—main "supporting cells" of the peripheral nervous system which wrap around axons of motor and sensory neurons—are octopus-shaped. The body of the cells lies beneath the outer layer of the skin, and there are longer extensions around the edge of the nerve cells that are pain sensitive, extending  up into the epidermis, the outer layer of the skin. Thus it collectively go to make up a mesh-like organ within the skin and remains sensitive to painful mechanical damage such as pricks and pressure.

Sensitivity to pain is required for survival and it has a protective function. It prompts reflex reactions that prevent damage to tissue, such as pulling your hand away when you feel a jab from a sharp object or when you burn yourself.

Activation of the organ results in electrical impulses in the nervous system that result in reflex reactions and an experience of pain, the researchers said.

Researchers find way to make cancer cells self-destruct

In a new hope for cancer patients, researchers have found a way to cause some cancer cells to self-destruct. 

The research team has identified a new pathway that works as a partner to a gene called MYC which controls normal cell growth, but when it is mutated or amplified in cancer, it sets off a chain reaction that helps tumours grow uncontrollably. 

The pathway involves a protein called ATF4, and when it's blocked, it can cause cancer cells to produce too much protein and die. 

The study done on mice points the way towards a new therapeutic approach as inhibitors that can block synthesis of ATF4 already exist. 

"What we've learned is that we need to go further downstream to block tumour growth in a way that cancer cells can't easily escape, and our study identifies the target to do just that," said a Professor.

According to researchers, this finding shows the alternative approach is to target ATF4 itself, since it's the point where both signal pathways converge, meaning there's less redundancy built in to allow cancer to survive.

 It also shows that ATF4 turns on the genes MYC needs for growth and also controls the rate at which cells make specific proteins called 4E-BP. 

This study also found that when tumours in humans are driven by MYC, ATF4 and its protein partner 4E-BP are also overly expressed, which is further evidence that these findings may point to an approach that could work for humans. 

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7 Symptoms That May Indicate Blocked Arteries

Many people believe that blocked arteries are a problem only for the elderly and those who are overweight, but it turns out that this phenomenon is commonplace, and according to a study, many people up to age 20 in the Western world already suffer from it. Because this is the case, the sweeping recommendation is to go and be examined as early as possible, especially if you experience one or more of the 7 symptoms listed in this article. Another thing you should know is that the abnormal flow of blood may also be a side effect of other serious health problems that should be noted since proper diagnosis and treatment can prevent a disaster.

1. Pain in the calve, hip and thigh muscles

Peripheral artery disease is a common circulatory blood problem in which limited arteries cause reduced blood flow to the limbs and are a major cause of leg pain, especially while walking. This condition can cause reduced blood flow to the brain and heart, and of course to the area of the legs, hips and calve muscles. Another cause of these pains may be fatty deposits in the arteries (atherosclerosis) or blockage of arteries due to lipids. In most cases, the area of pain indicates where the clot or block is located, which helps identify the root of the problem, but there are also other ways to identify it and its sources, such as numbness or weakness in the legs, skin discoloration, shiny skin, and impotence in men.

2. Chest pain

Chest pain or angina (angina pectoris) is the result of reduced blood flow to the heart. Severe pain in the chest, numbness in the left hand, heaviness, chest tightness or burning during physical or emotional exertion can be seen as a sign that one is actually suffering from arterial obstruction that requires examination, follow-up and treatment as it may be a precursor to a heart attack. There are other identifying signs that require a more thorough investigation, including chest contractions that radiate to the back, neck, jaw, shoulders, and arms, and especially to the left arm. These pains can be accompanied by shortness of breath, dizziness, and nausea, and they increase after exercise.

3. Temporary loss of vision in one eye

There are two main arteries leading blood and oxygen to the brain - one on the right and one on the left side of the neck, and they are responsible for delivering these vital substances to both sides of the brain respectively. When there is little blood flow or blockage in one of these arteries, insufficient oxygen reaches the eyes and brain, and as a result, their function can be damaged. In the case of reduced blood flow through one of these arteries, a temporary loss of vision may occur in the eye on the same side where the blockage exists, creating a screen over the eye and obscuring vision, usually only for a minute or two. Obstruction of both arteries can lead to stroke and even total vision loss, and to prevent this phenomenon you must maintain normal blood pressure and weight, a healthy lifestyle including proper nutrition, periodic examinations with a professional ophthalmologist and reporting on andy family history of arterial disease.

4. Lower back pain

Back problems are the second leading cause of disability and even loss of working capacity in various parts of the world, with 10% of people under the age of 20 in developed countries already having progressive obstruction of the aorta, causing problems of blockage in the arteries of the waist leading to various back problems. If you experience pain in the lower part of your back, you should know not to ignore them because they often indicate low blood flow that can cause herniated discs leading to pain and muscle contraction.

5. Shortness of breath

Shortness of breath occurs when coronary arteries are damaged or blocked, and people experience it when their heart is unable to pump enough blood to meet their body’s needs. The function of the coronary arteries is to supply blood to the heart, its muscles, its electrical conduction system, and its other components. Researchers have found that when a person experiences shortness of breath without chest pain, it can be a sign of a high-risk heart disease that requires medical attention. So, if you’re experiencing shortness of breath, and not just after exerting effort, you should be careful about what is causing it, making sure to check that it isn’t something that can worsen.

6. Cold feet or hands

The phenomenon of cold hands or feet throughout the year, or particularly cold hands during the winter, indicates a lack of blood - but not necessarily due to vitamin B12 deficiency in the body, rather as a result of partial obstruction or narrowing of the peripheral arteries that lead the blood to the extremities. If you are suffering from this condition, you should pay attention and check to see if you experience any other symptoms that indicate a lack of blood, such as weakening of pulse in the legs, long healing time in the case of a sore or a cut in the limbs, leg pain at rest or while walking, hair loss in the legs and feet, and of course a change in color of skin.

7. Fatigue and dizziness

Many attribute dizziness and fatigue they experience to lack of sleep or sleep disorders of some kind, which turns out to be true in most cases. However, according to a study, there are few cases where fatigue can indicate disorders in blood flow to various organs, especially the heart and brain, and are a sign of the possibility of arterial disease. The inability of the body to transfer blood properly reduces the amount of oxygen flowing throughout the body causing low functioning. It should be noted that according to various experts, a constant feeling of tiredness and frequent dizziness that indicates arterial obstruction is more common among women.

What increases the risk of blocked arteries?

One of the most common causes of clogged arteries is atherosclerosis; The pathogenesis of this disease isn’t known for sure, but it is clear that this is a complex disease that can start from childhood and develop rapidly as age progresses. Atherosclerosis can occur when certain factors damage the inner layers of the arteries such as smoking, high blood cholesterol, high blood pressure, high blood sugar or diabetes. To reduce the risk of side effects of poor blood circulation, you should exercise daily, lose weight, maintain a healthy, low-fat diet, quit smoking, and get checked at least once a year.

THIS IS ONLY FOR INFORMATION, ALWAYS CONSULT YOU PHYSICIAN BEFORE HAVING ANY PARTICULAR FOOD/ MEDICATION/EXERCISE/OTHER REMEDIES.                                    PS- THOSE INTERESTED IN RECIPES ARE FREE TO  VIEW MY BLOG-                                                                                           https://gseasyrecipes.blogspot.com/       
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