Candidate substance for COVID-19 treatment founded in nature

[Photo provided = IBS]

The COVID-19 treatment supplies the infected cells with tools to fight the virus. Therefore it is complementary to vaccines that have a virus defense system in advance. Unlike antibiotics that target bacteria in the body antiviral drugs are not designed to destroy virus particles. The outer skin of a virus has almost the same composition as the cell membrane of the host cell which can damage the host cell in an attempt to destroy the virus. In other words it is to prevent the situation of burning houses to get rid of the bedbugs (‘Don’t throw the baby out with the bathwater‘).

Instead the development of drugs to treat viral diseases takes a strategy to target one or more stages in the history of viral life. In order to understand the principle of action of COVID-19 treatment it is necessary to first observe the life history of SARS Corona Virus-2 living in the host.

SARS Corona Virus-2 uses the surface protrusions (Spike proteins) to bind to ACE2 receptors in human cells and infiltrate into the cells. After that fusion between the outer capsule of the virus and the cell membrane of the host cell occurs and genomic RNA (gRNA) which is a genetic material enters as the cytoplasm of the human cell. In the early stages enzymes from human cells are used to make necessary proteins. RNA polymerase (RdRp) one of the proteins produced at this time plays a key role in virus growth. The viral RNA is replicated in large quantities to create viral structures. Eventually these are combined into the whole body of the corona virus inside the human body and go out of the cell.

Such substances that inhibit the growth of the virus at any stage in the life history of the virus have the effect of suppressing the growth of the virus. In other words it is expected to have a therapeutic effect against the SARS Corona Virus-2. For example antibody therapy sticks to spike proteins to prevent binding of spike proteins to ACE2 which is the first step in life history. Remdesivir the first approved treatment for COVID-19 binds to RNA polymerase and inhibits replication while Chloroquine and Hydroxychloroquine which were in the limelight early in the pandemic prevent the release of SARS Corona Virus-2 gRNA (Webliography COVID-19 Scientific Report 2 Vol. 8).

Lets take a closer look at the process of SARS Corona Virus-2 entering the cell after binding to ACE2. The spike protein bound to ACE2 is cleaved by the cells proteolytic enzyme exposing the S2 site of the spike protein to the outside. This part plays intermediate role of the fusion of the outer skin of SARS Corona Virus-2 and the cell membrane.

Spike proteins are cleaved by cathepsin located in endosomes or lysosomes in cells or by a proteolytic enzyme called TMPRSS2 located in cell membranes. If the activity of these proteolytic enzymes is suppressed the membrane fusion stage can be inhibited and the cell penetration of the virus can be blocked. The chloroquine and hydroxychloroquine described above increase the acidity of endosomes and inhibit cathepsin activity while drugs such as ‘Camostat’ and ‘Napamostat’ are typical TMPRSS2 inhibitors. For your information the WHO has announced that chloroquine-related drugs are not clarified in effectiveness in treating COVID-19 and clinical trials using TMPRSS2 inhibitors are currently underway. This is the same in Korea. The inhibitors of TMPRSS2 include ‘Nafabelltan’ from Chong Kun Dang Pharmaceutical Corp. ‘Futhan’ from SK Chemical ‘Foistar’ tablets from Daewoong Pharm. Co. Ltd. and ‘CG-CAM20’ from Crystal Genomics Inc..

Historically humans have overcome many diseases by searching for drugs in nature and developing drugs. Aspirin and penicillin are typical. Aspirin is derived from salicylic acid extracted from willow bark and penicillin is derived from blue mold. Recently Chinese Professor You-you Tu discovered the malaria drug ‘Artemisinin’ in Artemisia annua (Sweet wormwood) a traditional herb medicine. Professor You-you Tu was awarded the Nobel Prize in Physiology or Medicine in 2015 for her contribution to malaria eradication.

Natural remedies are easily accessible around us and have the advantage of being used for hundreds to thousands of years proving its safety. Among them efforts to find natural products with antiviral effects have been ongoing for a long time. However it is still difficult to find a substance that can be released confidently just because it is a natural virus treatment.

Lets take a look at the case of Tamiflu a flu treatment developed by Gilead Sciences in the U.S. in 1996. Tamiflu also known as a cure for the new influenza (Novel swine-origin influenza A(H1N1)) which is derived from shikimic acid in Illicium verum a native Chinese plant. However Tamiflu is not a natural antiviral drug. Tamiflu is made from shikimic acid and multistep chemical synthesis. However shikimic acid is used for a synthetic starting material and does not have any antiviral activity. This means that Illicium verum tea does not provide a cure or preventive effect against influenza.

Meanwhile a research team at the medical school of Frankfurt University in Germany reported to the medical journal ‘Lancet’ that glycyridine the ingredient in licorice suppresses the reproduction of the SARS Corona Virus (Cinatl et al. 2003). However unlike the big response to the thesis it did not lead to the actual development of drug.

Since the outbreak of COVID-19 many researchers around the world are struggling to find natural products with anti-SARS Corona Virus-2 activity. The initial research just shown a possibility but recently significant research has been reported.

One of the most remarkable is ‘Plitidepsin’ developed by the Spanish pharmaceutical company PharmaMar S.A.. Plitidepsin is a substance isolated from the Aplidium which is a part of Aplidium albicans. Originally it was a treatment for multiple myeloma but it was tested at the level of drug regeneration and confirmed the possibility of COVID-19. IC50 (A medicine concentration that inhibits corona virus activity by 50%) in monkey kidney cells (VERO) is less than 1nM. In the experiment on mice expressing human ACE2 receptors it has also been shown to significantly reduce infection of the SARS Corona Virus-2 (White et al. 2021).

Platycodon grandiflorus is a natural medicine traditionally used in East Asia including Korea. Like candied or baked balloon flowers it is also used as food in Korea. It is widely known for its effects on pharyngitis coughs caused by cold phlegm and bronchitis it is because of the ingredient called playcodin D. Platycodine D is a type of triterpenoid saponins abundant in balloon flowers.

IBS Center for Cognition and Sociality has started a study on the treatment effects of ‘COVID-19’ of ‘Platycodine D’ which is effective in treating respiratory diseases and COVID-19 is also an acute respiratory disease. First of all Korean researchers created a ‘Fake virus’ that resembles SARS Corona Virus-2. This virus called pseudovirus expresses spike protein like ‘SARS Corona Virus-2.’ To study living viruses 3rd grade biological safety research facility is needed but pseudovirus can also be tested in 2nd biological safety facilities. Pseudoviruses also have only spike proteins that are involved in the entry into cells among various components of SARS Corona Virus-2. Therefore it is advantageous to selectively measure virus penetration or infectivity.

As previously explained in the history of life cleaving of spike proteins due to cathepsin or TMPRSS2 and fusion of virus-cell membranes are required for SARS Corona Virus-2 to get into cells. Chloroquine and hydroxychloroquine have failed in many clinical trials because they have been successful in reducing cathepsin activity but have not been able to prevent entry by TMPRSS2 (Hoffman et al. 2020). Other inhibitors targeting TMPRSS2 also have inherent limitations in preventing viral infection through endosomes.

The team attempted to replicate the pathways of entry of SARS Corona Virus-2 by cathepsin and TMPRSS2 in cells. ACE2 or ACE2+TMPRSS2 is expressed in the human lung cell line (H1299) to analyze the infection inhibiting effect of platycodine D. As a result it was discovered that platycodine D effectively inhibits both different approach paths. This means that the SARS Corona Virus-2 can be blocked by any path used to penetrate cells.

They selected ‘Yonggaksan’ and ‘Balloon flower marmalade’ from among natural medicines and foods containing balloon flowers as the main ingredients and measured the effectiveness of COVID-19 treatment. As a result the effect of suppressing the infection of SARS Corona Virus-2 was observed even at a very low concentration. On the other hand in an experiment comparing the efficacy of ginsenoside which is a ginseng saponin only platycodine D was effective. The anti-SARS Corona Virus-2 effect is a characteristic of the saponin ‘Platicodine D’ found only in balloon flowers.

Similar results have been obtained not only in pseudovirus but also in experiments using alive infectious SARS Corona Virus-2. Compared to existing anti-entry agents (Chloroquine camostat nafamostat etc.) it was confirmed again that platycodine D is the only one that effectively blocks both two SARS Corona Virus-2 cell infections.

Then why is platycodine D the only one that shows such activity? The analysis result revealed that the central structure of platycodine D is very similar to cholesterol which is a major component of cell membranes. In other words the structure is similar to cholesterol with sugar on both sides. If a cell accepts platycodine D into the cell membrane like cholesterol and the long sugar portion of the platycodine sticks out of the cell membrane this portion blocks membrane fusion which is an essential process of viral infection.

The research team suggested the possibility that platycodine D could be a candidate drug for a new COVID-19 treatment that prevents both virus penetrations. This overcomes the limitations of the candidate drugs that are currently under development. The results of the study are now in Bio archive (Kim et al. 2020).

A recent study has shown that ACE2 and TMPRSS2 the receptors in SARS Corona Virus-2 more exist in upper respiratory epithelial cells including nose than in lungs (Sungnak et al. 2020; Houet al. 2020). These findings mean that the amount of SARS Corona Virus (Viral load) increases rapidly from the upper respiratory in the early stages of COVID-19 causing anosmia and asymptomatic infection and then descends to the lower respiratory to infect lungs. This means that if the infection of the SARS Corona Virus-2 in body is prevented in the upper respiratory the disease can be treated in the early stages without progressing to severe conditions.

[Photo provided = IBS]

[Photo provided = IBS]

[Photo provided = IBS]

Website: : http://www.wip-news.com/news/articleView.html?idxno=6202