Antiviral Mechanisms of Traditional Chinese Medicine

About Viruses

A virus is made up of nucleic acid (DNA or RNA) and protein. Existing in a non-cellular structure, it is a pseudo-living organism that does not exhibit characteristics of a living organism. It needs host cells to survive. It is a special entity that is neither living nor non-living. It consists of a DNA or RNA strand enveloped in a protective covering. By infecting a host, this very simple organism can gain entry into a host cell for self-replication. However, it cannot replicate or live independently of a host cell. A virus can infect almost all types of cells. It can only multiply in a living cell by harnessing its cellular processes and energy. Strictly an intracellular parasite, viruses are resistant to antibiotics, making the latter ineffective or insignificant in viral therapy. Viruses can be classified by the presence of RNA or DNA, or by the route of infection into respiratory viruses, gastrointestinal viruses etc. Common viruses include rhinovirus, respiratory syncytial virus, influenza virus and parainfluenza virus, rotavirus, EB virus, Coxsackie virus and so on. Viruses are usually made up of 2 to 3 components. All of them contain genetic materials (RNA or DNA, but prions that contain only protein are not viruses). All viruses have an outer protein coat to envelop and protect the genetic materials within. Apart from that, some viruses can form a lipid envelope when they come into contact with cell surface. Appearing in various shapes and sizes, viruses can be helices, icosahedrons or more complex structures. Viral particles are about one thousandth the size of bacteria.

 

The origin of viruses has remained elusive so far. It is postulated that different viruses might have originated from different mechanisms. While some viruses might have originated from plasmids (a circular DNA that can be replicated within and transferred between cells), others might have originated from bacteria.

 

Infection Principles of Viruses

Viruses have a well-planned scheme to infect cells. There exist unique proteins or glycoproteins on different virus surfaces. These proteins or glycoproteins, acting as keys, combine with specific receptors on host cells to gain entry.

 

A lot of viruses exhibit a unique replication process, a point that is utilized by pharmaceutical companies to develop synthetic drugs to fight viral infections. For example, nucleotide analogues can interfere with viral replication. However, since the normal metabolic pathways of the host cells are involved in viral replication, the above-mentioned approach will also affect the health status of the host cells. As such, most current antiviral drugs evoke obvious adverse reactions, thereby compromising patient compliance. For example, Acyclovir used in herpes zoster treatment can cause symptoms like rashes and gastrointestinal discomfort, while the AIDS medicine Zidovudine engenders side effects such as anaemia and insomnia. In addition, viruses exhibit the following four characteristics that enhance their ability to evolve, namely:

1. High variability in genetic material

2. Multiple infection routes

3. High efficiency replication power

4. Long-term viability in host cells

These properties make viruses extremely resistant to chemically synthesized antivirals, and that is why we must look for new antiviral drugs.

 

Antiviral Mechanisms of Traditional Chinese Medicine

According to application experience for thousands of years, we know that the curative effects of traditional Chinese medicine spring from improving and nursing the body constitution, making it a suitable complement to overcome insufficiencies of western medicine, e.g. in tumours, viral infections, bacterial infections, immune disorders etc. There have been a lot of active ingredients extracted from hundreds of Chinese herbs involved in antiviral studies, the important ones of which include:

 

1. Flavonoids

Flavonoids, a group of low molecular weight polyphenolics, are found in all sorts of plants, e.g. vegetables, tea, cereals, barks, roots, stems, flowers etc. Flavonoids from different plants exhibit different bioactivities. Numerous studies have proven that flavonoids exhibit anti-tumour, anti-oxidant, anti-inflammatory as well as analgesic properties, making it a natural choice for scholars to look for antiviral remedies. Glycyrrhizin (liquiritigenin) and isoliquiritigenin extracted from leguminous plants Glycyrrhiza are flavonoids which exert a strong anti-HIV effect. Baicalein, a Baicalein plant extract, is also a flavonoid. Studies have shown that it exerts anti-inflammatory and anti-HIV activities by interfering with HIV’s ability to bind to CD4 cells, thereby preventing HIV from entering the latter.

 

2. Terpenoid

Presently, over 22000 types of terpenoids are known to exist in the plant and animal kingdoms. Terpenoids have significant physiological activities, acting as expectorant, cough suppressant, wind expellant, sweat promoter, anthelmintic and analgesic, and are important sources for natural products research as well as new medicine development. According to studies, terpenoids exhibit antiviral effects. For instance, a triterpene compounds extracted from licorice—glycyrrhizin--employs two mechanisms against HIV, one way by inhibiting the HIV replication process, and the other by preventing the virus's binding to host cells.

 

3. Essential Oils

Essential oils, comprising monoterpenes and semiterpenoids, is a collective term for volatile components that are present in plants. Emitting a pungent aroma, this collective group of water insoluble compounds is obtained through distillation. There are many Chinese herbs teeming with essential oils, with distinct examples like mint, fennel, Rhizoma Chuanxiong, Radix auckladiae, cinnamon etc. Most Chinese herbs containing essential oils, or extracts of essential oils, promote sweating, enhance energy flow, alleviate pain, suppress bacteria and enhance the flavour of food. Numerous studies have shown that essential oils can effectively inhibit viral growth. A good example is zedoary turmeric oil, a volatile component of zedoary turmeric and turmeric, which exhibits a direct inhibitory effect on respiratory syncytial virus (RSV) and a direct killing effect on influenza virus.

 

4. Anthraquinones

Anthraquinones commonly exist as plant metabolites. They exhibit anti-inflammatory, anti-swelling, analgesic, anti-itch and anti-bacterial effects. Studies have revealed that anthraquinones such as Rhein and Emodin exert an inhibitory action on various viruses such as HIV and Coxsackie virus B3 (CVB3). They can kill viruses directly, suppress viral replication as well as increase interferon synthesis. Meanwhile, when Emodin is added to drugged cultures of drug-resistant viruses, the ED50 (50% effective dose) is markedly increased.

 

5. Polysaccharides

Polysaccharides, one of the essential components of life, are macromolecular substances existing widely in nature. Studies have proven that polysaccharides and their derivatives can block the entry of viruses into host cells. The primary mechanism of this action lies in polysaccharides’ ability to affect surface proteins of viruses, thereby blocking their adherence onto, and hence entry into, host cells. In addition, polysaccharides can combine with immune cell receptors (toll-like receptors or TLR) to regulate immune functions and boost immunity. According to studies, Fucose, the main component in Sargassum horneri, can inhibit viral adherence and entry into host cells by altering the charges of viral glycoprotein or changing the shape of host cell receptors, thereby jeopardizing the interaction between viruses and host cells. Aloe polymannose, found in Aloe vera, can increase the population of protective antibodies against Picornaviridae infection.

 

6. Alkaloids

Alkaloids, organic compounds containing nitrogen, are commonly found in plants. Alkaline in nature, most alkaloids exist in a complex ring structure that envelops the nitrogen element within. They show marked bioactivities and represent one of the most important active ingredients in Chinese herbs.

 

Matrine alkaloid extract:Matrine exerts an anti-HBV action by reducing hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) levels in the liver of HBV transgenic mice. Apart from that, Lamivudine and Matrine show a marked inhibitory action on HBV replication. Besides its antiviral actions, it has been known that Matrine can also work with other antiviral drugs to achieve more effective therapeutic effects.

 

All the above-mentioned ingredients show antiviral properties. Through different cross experiments and comparisons, it has been discovered that the extracts of these Chinese herbs exert complementary or similar antiviral mechanisms against DNA viruses, RNA viruses and retroviruses.

 

There is a multitude of studies to prove the antiviral properties of Chinese herbs. From these reports, it can be concluded that the antiviral mechanisms of traditional Chinese medicine include:

1. Blocking virus entry into host cells

2. Inhibition of viral replication

3. Regulation of host cell immunity

 

1. Blocking virus entry into host cells

The first step of a virus’s life cycle involves breaking entry into a host cell by combining with specific receptors on the cell membrane. If we can stop this critical step, we can effectively block virus entry. There are already papers on cellular experiments to assert that Chinese herbs can effectively block virus entry, and among them:

1. Radix achyranthis bidentatae—its root extract can combine with the surface glycoprotein of herpes simplex virus (HSV) and interfere with the latter’s ability to adhere to host cells.

2. Rhizoma cibotii and Spica prunellae—the whole-herb extract can inhibit the formation of a six-helix bundle of human immunodeficiency virus (HIV) gp 41, thereby robbing HIV’s ability to fuse with the host cell membrane./span>

3. Fructus arctii—its fruit extract can suppress influenza agglutination.

4. Radix et Rhizoma Rhei and Radix Polygoni Multiflor—concentrated extracts of these 2 herbs can impede the binding of the S protein of SARS-CoV to the ACE2 (Angiotensin converting enzyme 2) protein on the host cell membrane.

5. Radix glycyrrhizae (licorice)—its whole-herb extract can suppress viral attachment and penetration.

6. Fructus schisandrae—its fruit extract can inhibit the binding of viruses to the histoblood group antigen on epithelial membranes of small intestine cells.

 

2. Inhibition of viral replication

The life cycle of a virus, which centres round its replication process, involves the host cell’s metabolism. It has been known from numerous studies that Chinese herbs, the prominent examples of which are as shown below, can affect the virus’s protein functions, including viral protease, polymerase, integrase, reverse transcriptase etc. needed for viral replication.

1. Rhizoma coptidis—the whole-herb extract can suppress DNA synthesis in HSV virus.

2. Chrysanthemum morifolium—the floral extract can suppress HIV’s integrase functions.

3. Kadsura matsudai—the fruit extract, and the mono-component Trichosanthin from Trichosanthes kirilowi, can suppress HIV replication.

4. Radix scutellariae—the extract of the mono-component Wogonin can suppress polymerase function of Hepatitis B virus (HBV) in animal and cellular experiments.

5. Salvia miltiorrhiza—the mono-component protocatechuic aldehyde can suppress HBV replication.

6. Radix sophorae flavescentis—the mono-component Oxymatrine can reduce the expression of heat stress cognate 70 (HSC70), a protein required for hepatitis B viral (HBV) replication.

7. TXL (Tian Xian Liquid) can inhibit e-antigen (HBeAg) secretion, and significantly inhibit HBV replication.

8. Rhodiola kirilowii—the whole-herb extract can inhibit proteases of Hepatitis C virus (HCV).

9. Fructus arctii—the mono-component Arctigenin can inhibit influenza viral replication.

10. Radix glycyrrhizae— the mono-component Glycyrrhizin can inhibit SARS CoV replication.

 

3. Regulation of host cell immunity

Besides the direct actions mentioned above, the life cycle of a virus can also be affected by indirect antiviral mechanisms. For the virus to penetrate the host cell successfully, it must first evade the host’s immune responses. Hence indirect antiviral mechanisms can come in the form of:

 

Regulation of host cell immune responses, such as inducing interferon (IFN) secretion to inhibit viral replication. Numerous reports have revealed that Chinese herbs can effectively enhance the immune system, boost immunity and enable host cells to fight viral infection. For instance, honeysuckle with antipyretic and detoxifying effects can promote white blood cell phagocytosis and increase lymphocyte conversion rate. Animal experiments have shown that Scutellaria baicalensis can induce host cells to produce interferon and inhibit viral replication. There are other examples:

1. Rhizoma polygonati—both the whole-herb extract as well as the leaf and stem extract of Herba houttuyniae can regulate the immune responses to herpes virus (HSV).

2. Extracts of Radix sophorae flavescentis roots, Flos caryophylli leaves as well as Kadsura matsudai fruits can regulate immune responses to HBV.

3. Radix astragali polysaccharides (Astragalus polysaccharides) can regulate immune responses to FMDV (Foot-and-mouth Disease virus).

4. TXL (Tian Xian Liquid) exerts immunomodulatory effects on peripheral blood mononuclear PBMCs and T cells in patients with recurrent aphthous ulcer (RAU).

 

In the wake of rapid advancement in R&D technology, and through different extraction, separation, fermentation and other processes, it is found that Chinese medicine is rich in many active ingredients with antiviral activity, including flavonoids, terpenoids, essential oils, anthraquinones, polyphenols, polysaccharides, alkaloids etc. Apart from that, when Chinese medicine is used together with existing antiviral agents, it is found that, with the right combination, Chinese medicine with proven clinical evidence can help reduce the dosage of the antiviral agent used, thereby reducing the latter’s side effects and enhancing antiviral effects through synergy. At the moment, the use of Chinese medicine is limited to only a few Asian countries. As the saying goes, ‘to each his own’. But traditional Chinese medicine, with its long use history, has proven that it is safe, effective and economical. The experience of our ancestors can definitely be combined with today's science and technology to make a difference in combating pandemics.

References:

1. Wikipedia

2. The Pharmaceutical Journal, Book 125, Volume 31, Issue 4, pages 43-46

3. Taiwan Institute of Industrial Technology, Institute of Biotechnology and Medicine, December 20th, 2007 to February 29th, 2008 —TXL Inhibition of Hepatitis B Virus Activity Analysis Tests

4. The American Journal of Chinese Medicine, Book 32, Volume 2, June 2004 - Immunomodulating Effects of "Tien-Hsien Liquid" on Peripheral Blood Mononuclear Cells and T-Lymphocytes from Patients with Recurrent Aphthous Ulcerations