Introductory Chapter: An Intervention Therapeutic Strategies against SARS-CoV-2

1. Introduction

The objectives of this introductory chapter is to outline the possible intervention therapeutic strategies against SARS-CoV-2.

Upon such vision, all research projects, scientific creations, trouble-shooting and problem-solving techniques must be based on healthy environment. As a matter of fact, the environment has provided us with the best of everything, of food, water, air, and a cure for every illness. In our turn, we should make good use of God’s blessings bestowed upon us through natural sources by which we can fight contagious diseases including COVID-19.

Accordingly, the founding factors of this vision will be:

• Protect the environment against all hazards.

• Treat the current diseases by introducing totally indigenous thought, ideas, raw materials and technology to produce a safe, effective, and economic therapy.

• Spread hygienic awareness and good sound health practices as a protection against potential dangers.

• The premises of this vision are:

• A sound healthy environment embraces a sound and healthy society.

• A healthy environment provides us with a cure to any ailment.

• An unhealthy environment is the source of all illnesses.

2. A possible approach for intervention of SARS-CoV-2 infectivity

SARS-CoV-2 genomic RNA is protected by two envelopes: phospholipid bilayer and protein. The human cell entry by the virus was prompted upon S-protein (Spike protein), which resides in the envelope anchors to ACE2. Protease cleaved the S-protein into S-1 and S-2 fragments, whereas S-1 binds to ACE2. While S-2 was cleaved by serine protease enzyme (TMPRSS2), leading to membrane fusion. This may halt the first step of infection with the virus, as presented inFigure 1.

Figure 1.

SARS-CoV-2 entry to the host cell (airway cell) that initiates with the S-protein on its envelope and the endocytosis process. This illustrates the essentiality of ACE2 and TMPRSS2 in the SARS-CoV-2 infection.

3. Promising natural serine protease inhibitors

Serine proteases, including elastase, trypsin, and chymotrypsin, are a large class of enzymes and play various roles in human health, including blood coagulation and immune response. An increase or decrease in protease activity can induce pathologies, including inflammation, cancer, stroke, heart attack, and pancreatitis.

3.1 Halting of viral replication

3.1.1 Inhibition of SARS-CoV-2 NSP15 endoribonuclease

Nidoviral RNA uridylate-specific endoribonuclease (NendoU) is one of the enigmatic enzymes that is corresponding to Nsp15, carrying a C-terminal catalytic domain (EndoU family). They perform various biological functions related to RNA processing. All characterized family members display an RNA endonuclease activity [1].

Inhaled ciclesonide is expected to reduce viral replication and host inflammation in the lungs, with decreased immunosuppressive effects compared to systemic corticosteroids, as ciclesonide primarily remains in the lung tissue, and does not significantly enter the bloodstream. This is also considered to be another example of drug repurposing. Therefore, we could conclude that natural steroids are potential inhibitors [2].

3.1.2 SARS-CoV-2 main protease inhibitors (M^pro = 3CL^pro)

There are many examples of α-keto amides inhibitors of natural origin, such as eurystatin A and B (prolyl endopeptidase inhibitor), complestatin (HIV replication inhibitor), and aplidine (antitumor) (Figure 2) [3].

Figure 2.

Natural alpha-ketoamides could be used as strong inhibitors of viral proteases (M^pro).

4. The immunomodulation effect

The immunomodulation effect may be useful in controlling the cytokine storm that occurs late among critically ill SARS-CoV-2 infected patients.

It was reported among several patients. A noticeable elevation of both IL-6 and IL-10 levels in response to SARS-CoV-2 infection. Virus results in the increase in cytokines IL-6 and IL-10 [4]. This immune reaction may lead to a cytokine storm then followed by a failure of several body organs, which may lead to death. It was suggested that some chloroquine derivatives may retain immunomodulatory activity and may be able to subdue the reactions of an immune response. This may help in early intervention as well as avoid the most likely bad scenario of the infection to a life-threatening status [5].

Pro-inflammatory cytokines, for example, IL-6 and IL-10, may result in expression induced by LPS. However, modulating several intracellular signaling pathways in macrophages and halting LPS-induced cytokines production by decreasing the mRNA stability by suppressing ERK1/2 activation. This hypothesis could be accomplished by a series of naturally isolated compounds, for example, luteolin, syringic acid, apigenin, curcumin, and lichochalcone, at the transcriptional level [6].

In conclusion, there is always hope to find potent, safe, and economic therapeutic agents for the treatment and management of COVID-19 outbreak from the commonly abundant natural products, such as phytosterols, alpha-ketoamides, and flavonoids. However, these findings need further investigation and experimental studies to be approved, but this could open the door for the utilization of abundantly available natural products to provide a therapeutic strategy via developing safe, effective, and economic drugs against this pandemic.