Category: Nature

Nature, Technology

About infection inhibitors of the new coronavirus (SARS-CoV-2) as its therapeutic drugs: Are inhibitors on furin and transmembrane protease serine 2 etc. effective?

The S protein of the new coronavirus (SARS-CoV-2) is divided into S1 sites that bind to the host receptors and S2 sites for membrane fusion. The boundary site of this S1 site and S2 site has a furin cleavage site, and there is a target domain of transmembrane protease serine 2 (TMPRSS2) in the S2 site. The following research has been reported that the use of inhibitors on those proteases may be able to reduce the infection of the new coronavirus.
https://linkinghub.elsevier.com/retrieve/pii/S2211-1247(20)31243-2

decanoyl-RVKR-chlorometylketone (CMK) for a furin inhibitor, camostat for a TMPRSS2 inhibitor, as well as naphthofluorescein which inhibits RNA replication, were studied. VeroE6 cells are used for the experiments.

 

 

 

 

 
Obtained efficacy and toxicity were as follows; the 50% inhibitory concentration (IC50) was 0.057 μM for CMK, 9.025 μM for naphthofluorescein, and 0.025 μM for camostat. The 50% cytotoxic concentration (CC50) was 318.2 μM for CMK, 57.44 μM for naphthofluorescein, and 2,000 μM for camostat. The resulting selection index is 5,567 for CMK, 6.36 for naphthofluorescein, and 81,004 for camostat.

Note that there is a difference among these inhibitors, CMK and camostat prevent the initial infection of the virus, and naphthofluorescein prevents the replication of the virus. We look forward to further consideration as a lead compound for the development of therapeutic drugs in the future.

Nature, Technology

To suppress infection with the new coronavirus (SARS-CoV-2), pineapple intake will be GOOD.

The Univ. of Nebraska Medical Center group has reported a research finding that bromelain extracted from pineapples (enzyme classified as a cysteine protease in proteolytic enzymes) is effective in suppressing infection with the new coronavirus (SARS-Co-2).
https://www.biorxiv.org/content/10.1101/2020.09.16.297366v1

 

 

 

 

 

Bromelain targets angiotensin-converting enzyme 2 (ACE2), type II membrane-penetrating serine protease (TMPRSS2) and SARS-CoV-2 S-protein, and thereby suppresses SAS-CoV-2 infection. Because bromelain is well absorbed through digestive organs and maintains its biochemical activity in the body, it is said that ingesting pineapples rich in bromelain will suppress infection with the new coronavirus (SARS-CoV-2).

Nature

The new coronavirus (COVID-19) has a higher rate of severity in men than in women, but the rate of severity seems to skyrocket, especially in baldness.

In the new coronavirus (COVID-19), there are some reports that men are more likely to become more severe than women due to the effects of male hormones. The following studies have reported that men with baldness have a very high rate of severity among them.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387285/.

The following NHS-scale is used as the indicator of baldness.

 

 

 

 

It can be noted that the rate of severity get very high in NHS-scale from 3 to 7.

 

Nature, Technology

Biomarker research for pancreatic duct adenocarcinoma using its organoids

A group of Harvard Medical Schools has reported potential biomarkers for pancreatic duct adenocarcinoma using pancreatic duct adenocarcinoma derived organoids.

https://insight.jci.org/articles/view/135544

(1) From the viewpoint of glycans: High mannose and Lewis X epitope structures increase in pancreatic duct adenocarcinoma.

(2) From the viewpoint of extracellular vesicles (EV) proteins: ANXA11 (anexine A11: calcium-dependent phospholipid binding protein mobilized in the budding region of the transport endoplasmic reticulum COPII of the endoplasmic reticulum) is increased.

Let’s look forward to further research progress.

Nature

The D614G mutation in the S protein of the new coronavirus (SARS-CoV-2) causes increased infectability due to changes in Conformation of RBD (Receptor Binding Domain)

In the new coronavirus (SARS-CoV-2), viruses with D614G mutation in S proteins are now the mainstream of infection. A group of University of Massachusetts Medical School et al. has reported their findings on the causes of why D614G mutation is to be more infectious than the past D614.

ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492024/

Using SPR, the experimental results of the interaction between D614G and ACE2 indicate that it is not due to increased affinity of D614G mutation to ACE2 (rather, slightly affinity is lowered), Structural analysis of S proteins by cryo-EM shows that the presence rates of Close and Open status in RBD (Receptor Binding Domain) have changed, and that D614G mutation is more likely to have Open structures than D614. Therefore, it has been concluded that the increased infectivity of D614G is due to the more exposed RBD of the S protein.

Nature

A Proposal for the Treatment of New Coronavirus (SARS-CoV-2): Role of NK Cells

NK cells play an important role in viral infections. The University of Ferrari group proposes a treatment using anti-NKG2A antibodies based on the results of research on how NK cells behave in the case of a new coronavirus (SARS-CoV-2) infection.
https://pubmed.ncbi.nlm.nih.gov/32859121/

Infecting S protein of the new coronavirus (Spike 1 Protein and Spike 2 Protein) into lung epithelial cells and co-culturing with NK cells, they investigated the expression status of GATA3 (transcription factor), HLA-E (E class of human leukocyte antigen), NKG2A/CD94 (NK cell inhibitory receptor), CD107a (degranulation: release of cytotoxic factor), and IFN-gamma. As a result, it was found that the following expression changes occurred.

  1. GATA3’s Advances
  2. HLA-E’s Advance
  3. NKG2A/CD94’s Advance
  4. Decrease in CD107a
  5. Decrease in IFN-gamma

 

 

 

 

 

These changes are caused by SP1 (Spike 1 Protein) of the S protein. Sp1 infection activates the transcription factor GATA3 and presents the SP1 peptide (8mer) on the cell surface by HLA-E. The combined HLA-E and NKG2A/CD94 results in inhibitory signals in NK cells. At the same time, the release of cytotoxic factors has been suppressed, the release of IFN-gamma has been also suppressed, and thereby the immune system of virus elimination has been weakened.

Therefore, in conclusion, in the early stages of infection, it was proposed as a potentially effective treatment to dose anti-NKG2A antibody (monalizumab) in order to enhance immune activity.

Nature

How do glycans get involved in SARS-CoV-2 infection?

The second wave of the new corona virus infection is hitting. The number of new infections in Tokyo yesterday reached 472. There are 195 people in Osaka, 181 in Aichi, 121 in Fukuoka, more than 100 in large cities.

The speed of research on the new corona virus and the rapid increase in published papers are amazing. If the new corona virus (SRAS-CoV-2) infects humans, what are the receptors on cells that trigger the initiation of the infection? In response to the question, it is established that it must be ACE2 (Angiotensin Conversion Environment 2). For example, the following papers are helpful (but there are too many papers to be missed, please forgive me).

 

However, in addition to ACE2, there is a report that ANPEP (Alanyl Minopepptidase) and DPP4 (Dipeptidyl Peptidase-4) can also be such receptors.

 

There is little exception that membrane proteins are heavily glycosylated. And both the S protein of the new corona virus and ACE2, which is the infected receptor, are strongly glycosylated.
For example, in the following paper, it has been reported that various N-type glycans are expressed on S proteins, from Oligomannose to hybrid and Complex, and for O-type sugar chains, Core1 and Core2 type glycan structures are expressed.

 

On the other hand, for ACE2, an overview of the glycan modification is described in the following paper, and it can be seen that a very diverse glycans is expressed in the same way as the glycan modification of S protein.

 

In this way, considering that a variety of glycans are expressed both on the S protein and the receptor side, there should always be an infection start with a sugar chain.
In the following paper, it has been reported that S proteins strongly interact with DC-SIGN and MGL, which are C-type lectins, and also strongly interact with siglec-3, -9, and -10 sialic-3, -9, and -10, which are sialic acid binders.

 

Taking this information into consideration together, the infection of the new corona virus is not ACE2 one side down, but peptidases (ANPEP, DPP4), but C-type lectin (DC-SIGN, MGL), and Siglec may also be involved.
Moreover, these receptors are widely expressed in tissues in the body, including immune cells.

 

What is even more interesting is the report that ABO blood type is related to the severity of the new coronavirus.
From this paper, it can be found that people of type A are twice as severe as O-type humans. This suggests that anti-A antibodies may be suppressing sars-CoV-2 infections.
Since anti-A antibodies are for the following type A antigen, it is considered that there is no doubt that this type of glycan structure is involved in infection in some way.
Thumbnail image of ABO.png
Infectious diseases cannot be talked about without glycans, I think.

 

Furthermore, it is so mysterious that there must be an unknown Factor-X to explain everything reasonably; why mortality rates in Asia and Oceania are so low comparing with those of Europe and America.