This unpublished post by Erboristeriacomo.it aims to bring together the scientific studies on COVID19 drawn up on the basis of the studies and data obtained thanks to molecular biology for about 2 years since the pandemic began. Here is Covid19 what it is and how it works, its mechanisms of action. Finally, here is some latest news on pharmacological and phytotherapeutic research.
COVID-19: a very long pandemic
Coronavirus disease 2019 (COVID-19) originated in Wuhan (Hubei province, China) in December 2019. It is an infectious respiratory disease caused by the virus called SARS-CoV-2. Since then, the disease has spread globally, reaching pandemic proportions. The publication of the COVID-19 genetic sequence in January 2020 facilitated the rapid development of test kits (rapid, molecular, serological). In addition to the serums on the market, several studies are currently underway around the world to discover effective drugs to prevent infection, eradicate the virus and manage complications of the disease.
So far, since the start of the pandemic, patients with COVID-19 have been treated with antiviral drugs, protease inhibitors, anti-inflammatories (e.g. ibuprofen), antimalarials, neuraminidase inhibitors, ACE2-based peptides, 3-chymotrypsin protease inhibitors -similar, papain-like protease inhibitors, etc. Clinical studies are ongoing on the efficacy of many of these drugs; however, we currently know that the best potential pharmacological targets are: the main protease Mpro, the Spike protein (S) and the RNA dependent RNApolymerase (RdRp).
Researchers are also studying alternative herbal therapies due to their possible antiviral and anti-inflammatory activity to fight infections caused by coronaviruses. In fact, until now their role has been confined to strengthening the immune system and prevention.
Knowing the new Coronavirus: what t is and Covid 19 how is made
The pathogen responsible for the pandemic belongs to the Coronavirinae subfamily in the Coronaviridae family of the order Nidovirales. Prior to its appearance, two highly pathogenic ß-coronaviruses in humans had already been identified: SARS-CoV and Middle East acute respiratory syndrome coronavirus (MERS-CoV). The latter causes severe types of lower respiratory tract infection and acute respiratory distress syndromes (ARDS). The new betacoronavirus, called SARS-CoV-2, shares 79% genome sequence identity with SARS-CoV and 50% with MERS-CoV24.
SARS-CoV-2 is a novel positive-polarity-enveloped RNA β-coronavirus and a single-stranded RNA genome consisting of 30 kb. The viral particle is 60-100 nm in diameter and appears round or oval. The CoV-2 virion has a nucleocapsid composed of genomic RNA; it is covered with phosphorylated proteins that interact with the viral membrane during virion assembly, playing a critical role in enhancing virus replication. The genomic RNA and the nucleocapsid are wrapped in a double layer of phospholipids; several proteins are immersed in this layer that play crucial roles for infection and replication, here they are in this figure that represents COVID 19:
Viruses, like this one, continually evolve the proteins on their surface to enhance the interaction with the receptors on the cells and enter them more efficiently according to the “key-lock model”. In this case:
- the protein S (spike) of CoV2 (key)
- the human hACE2 receptor (the lock). This receptor is expressed in various organs such as lung, heart, kidney, intestine, gall bladder and testicular tissues; it is normally used by our body for the correct functioning of the kidney, heart, blood vessels and lungs. However, it also turned out to be the main gateway to the virus. In fact, Covid-19 uses the same human receptor as SARS-CoV.
Covid19 how is made: What is protein S and how infection occurs
Protein S (Spike) is the one that “decorates” the surface of the virus and is responsible for the corona appearance of the viral surface, hence the name Coronavirus. It is a transmembrane trimeric protein made up of three identical units called protomers. Each protomer exposes to the outside of the chains of sugars that serve to fool the immune system. Each Spike protomer comprises 2 functional subunits:
S1: is responsible for binding to the receptor on target cells. This subunit contains:
- an N-terminal domain,
- two subdomains SD1 and SD2,
- the receptor binding domain (RBD) responsible for binding to the host cell through interaction with ACE2 (the “gateway to the virus”). Furthermore, again in the RBD but upstream of the interaction domain with ACE2, the Spike has a sequence of specific amino acids recognized by another class of receptors, the integrins. This sequence may have evolved as an alternative mechanism of entry for the virus or to broaden its tropism.
- a C-terminal domain that contains a fusion machinery that helps the virus enter cells.
S2: is involved in fusion with the cell membrane.
Spike protein: its role
Spike protein is among those that contribute to host receptor binding and viral pathogenesis. Protein S:
- it is used by the virus as a key to enter host cells;
- acts by binding the receptor on target cells; induces endocytosis of virions; catalyzes the fusion between cellular and viral membranes, ensuring the entry of viral genomic RNA into the cytoplasm of cells;
- it is also the main target of the immune system, activating it and inducing the production of antibodies.
CoV-2 protein S exists in two different conformations, called “up” (up) and “down” (down). In the “down” conformation, CoV-2-S cannot mediate the fusion of CoV-2 with the host cell membrane. To ensure the entry of the virus, it must undergo a conformational change, which guarantees the acquisition of the “up” conformation.
Covid-19: how the infection occurs
The entry of the coronavirus into susceptible cells is a complex process that requires the concerted action of binding to the receptor and the proteolytic processing of protein S to promote fusion between the virus and the cell. Basically: the acquisition of the “up” conformation occurs as soon as the Spike CoV-2 protein approaches ACE2; then, the cut by cellular proteases takes place in the S1 / S2 site: the cut occurs at the boundary between the S1 and S2 subunits, generating two separate regions that remain non-covalently linked in the so-called “pre-fusion conformation”. After the cut, the S1 and S2 subunits perform different functions:
- S1 binds ACE2 through RBD;
- S2 mediates the entry of the virus after a further cut at a secondary site called S2 ‘. This cut is thought to activate membrane fusion through another extensive and irreversible conformational change (“post-fusion conformation”), causing infection.
Binding of protein S to the angiotensin converting enzyme 2 (ACE2) receptor initiates three major pathways: (1) inflammation, (2) clotting, and (3) bradykinin cascades. The development of inflammation leads to the massive activation of both neutrophils, dendritic cells and macrophages that are mobilized at the site of infection. This first line of defense cells increases the production of chemokines and cytokines that favor the onset of inflammation (cytokine storm).
The best known responsible cell proteases
One of the cellular proteases involved in the entry of CoV-2 into host cells is the transmembrane serine protease 2 (TMPRSS2), which is also required for SARS-CoV infection. In fact, the inhibition of TMPRS22 blocks the entry of SARS-CoV and CoV-2 into cells.
Furthermore, it is interesting that the Spike CoV-2 protein possesses an insertion of four amino acids at the boundary between S1 and S2 compared to the SARS-CoV protein S. These four additional amino acids make up the cleavage site for a specific human protease: furin. It has recently been shown that, like TMPRSS2, furin is essential for the entry of CoV-2 into host cells. The presence of this peculiar cleavage site for furin in CoV-2-S has also led to the hypothesis that, given the practically ubiquitous expression of furin-like proteases, they could have participated: in the acquisition of the broader cell and tissue tropism of CoV-2 compared to SARS-CoV; to an increase in its transmissibility and pathogenicity.
How Covid 19 acts: this is how the Coronavirus replicates itself
During host cell infection, the viral genome acts as messenger RNA and directs the synthesis of two large polyproteins (pp1a and pp1ab). They contain within them smaller proteins necessary for the production of new viral particles inside infected cells. This set of proteins includes:
- a replication / transcription complex,
- different structural proteins needed to build virions
- two proteases, which cut the two large polyproteins into smaller functional proteins near the peptide bonds. The main protease of the SARS-CoV-2 virus is the 3-C-like protease (Mpro). It is a cysteine enzyme essential for viral replication and transcription, and is currently one of the potential targets for antiviral therapy.
CoV-2 positive RNA replication is mediated by a multiprotein complex composed of non-structural proteins (nsp), encoded by the virus but expressed only in infected cells. These include various enzymes and transcription factors that ensure the virus has the ability to replicate and produce many copies of itself. The basic component of this complex is the nsp12 catalytic subunit: it alone has little ability to bind the RNA template; in fact, to activate it needs to link the accessory factors nsp7 and nsp8. Cov2 nsp12-nsp7-nsp8 complex provided the overall structure of RdRp (RNA dependent RNA polymerase). Given the key role of this molecular machinery in viral replication, the RdRp polymersase has been proposed as the target of a class of antiviral drugs, including remdesvir.
Covid19 what it is and how it works: the most serious symptoms listed so far and why
Acute Distress Syndrome
Patients with severe SARS-CoV-2 infection have elevated levels of pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-7, IL-8, IL-9, IL-10 and TNFα, and chemokines in plasma. Most patients also develop marked lymphopenia; the T cell count is significantly reduced and the surviving T cells appear to be functionally depleted. Cytokine storm syndrome causes acute respiratory distress syndrome and respiratory failure, which is considered a leading cause of death in COVID-19 patients.
The coagulation disorders
As a consequence of increased cytokine levels, a common feature in COVID-19 patients are coagulation disorders, elevated venous thrombo-embolism, and disseminated intravascular coagulation (DIC). Preliminary reports on clinical and laboratory findings of COVID-19 patients indicate: thrombocytopenia, elevated D-dimer and fibrinogen levels, prolonged prothrombin time, and disseminated intravascular coagulation. Additionally, early studies have suggested that elevated levels of circulating D-dimer (a cross-linked fibrin product) are associated with mortality among COVID-19 patients.
Pneumonia and edema
Pathological pulmonary findings suggested that early SARS-CoV-2 pneumonia-induced pathological changes include pathological interstitial pneumonia and prominent pulmonary edema, with protein exudation and minor inflammatory cell infiltration. One of the postulated hypotheses explaining the development of pulmonary edema suggests that the suppression of the receptor (ACE-2) by the SARS-CoV-2 virus may: impair the hydrolysis of des-Arg9-bradykinin; stimulate the bradykinin type 1 (BKB1) receptor pathway to induce leakage of fluid into the lungs.
Covid 19 what it is, how it works: bromelain is among the substances being researched to relieve symptoms
Drugs being tested for reuse in the treatment of COVID-19 tend to fall into two categories: those that target the viral replication cycle and those that aim to control the symptoms of the disease. As for natural remedies, on the other hand, among the antivirals studied there were for example: naringenin (1), Pelargonium sidoides, Perilla (2). Bromelain has been added among the eligible remedies that would aim to control the symptoms of the disease.
Bromelain: uses and opportunities in the studio
Bromelain is so far known to the public as a good digestive if taken away from meals, or away from meals, thanks to its anti-edematous and anti-inflammatory properties, it can also be taken against cellulite (see the study: Multicenter study on the effectiveness of a supplement based on of bromelain and triterpenes from Centella Asiatica in the treatment of cellulite, Andrea Romani et. al., conducted by 45 Italian dermatologists, which you can find here). Pay attention to titration, on which the effectiveness of bromelain depends. However, its benefits don’t stop there.
It may be a promising candidate for the development of oral enzyme therapies for patients, particularly in the treatment of cardiovascular disease, blood clotting and fibrinolysis disorders, infectious diseases, inflammation-associated diseases and many types of cancer. Finally, few know that the latest research on natural substances against COVID-19 also focuses on bromelain. The multiplicity of beneficial effects of bromelain makes it one of the potential study candidates that could be classified in the category of substances that aim to control the symptoms of the disease. Here is what emerged from this study: “Beneficial Properties of Bromelain” – 9. Bromelain as a Possible Treatment for COVID-19 Disease.
Bromelain: Antiviral properties 
Bromelain is a cysteine protease capable of breaking disulfide bonds (present in both ACE2, TMPRSS2 and the Spike protein) and degrading proteins (Sagar et al. (2021); Akter et al.) The pre-treatment with bromelain it reduced viral infection and viral copies of SARS-CoV-2 RNA within cells. Bromelain also shows good binding affinity towards various variants of the receptor binding domain (RBD) responsible for the attachment of the virus to ACE2 (Tallei et al.). Therefore, it is assumed that bromelain can be used as a broad antiviral agent against SARS-CoV-2 and other related family members.
Bromelain: immunomodulating properties
In experimental studies, bromelain exhibits unique immunomodulatory actions. Bromelain potentially activates the healthy immune system in response to cellular stress by: activating the release of inflammatory mediators, including interleukin IL-1β, IL-6, interferon (INF) -γ and necrosis factor tumor (TNF) -α; modulation of T cell responses; increased T lymphocyte proliferation. Furthermore, bromelain can inhibit the secretion of IL-1β, IL-6 and TNF-α when immune cells are already stimulated in the condition of inflammation-induced cytokine overproduction.
Finally, through the downregulation of the pro-inflammatory prostaglandin PGE-2 through the inhibition of NF-κB and cyclooxygenase 2 (COX-2), bromelain can regulate the over-expressed immunogenic pathways and reduce lung inflammation. In light of the data that most deaths from COVID-19 are caused by the hyperinflammatory process (cytokine storm syndrome, which causes acute respiratory distress syndrome and respiratory failure), the beneficial effect of bromelain on the immune system appears to be promising in supporting / improving clinical outcomes among COVID-19 patients.
Bromelain: Anti-inflammatory and anti-edema properties
During animal studies, bromelain has been shown to improve inflammation and edema by hydrolysis of bradykinin and by reducing serum and tissue levels of kininogen and bradykinin. The ability of bromelain to inhibit the biosynthesis of kinines that promote the development of inflammation can alleviate not only mild symptoms of COVID-19 (such as cough, fever, pain), but also cytokine storm and clotting disorders, a of the main causes of multi-organ failure.
Bromelain: Antithrombotic, anti-inflammatory, anticolagulant properties
Bromelain prevents the formation of thrombosis, thrombophlebitis and fibrinolytic activities by stimulating the conversion of plasminogen to plasmin and preventing platelet aggregation. Thrombosis and clotting reduce the blood circulation of erythrocytes and affect the ventilation-perfusion rate in patients with COVID-19; they also lead to the development of acute respiratory distress syndrome. Therefore, the general role of bromelain is to improve cardiovascular and circulatory functions, mainly by decreasing coagulopathy and promoting the free flow of blood around the circulatory system. The anti-inflammatory and anticoagulant abilities of bromelain deserve significant scientific attention because they can prevent the escalation and progression of the COVID-19 disease. As shown in Figure (The structure of the SARS-CoV-2 virus and the interference of multiple activity of bromelain (B) in the crucial steps of COVID-19 pathophysiology), bromelain can interfere in the crucial phases of the pathophysiology of COVID-19 .
Bromelain: Antimicrobial, antifungal and antibacterial properties
The antimicrobial, antifungal, and antibacterial properties of bromelain appear to be useful in the treatment of co-infections in COVID-19 patients. Since bromelain can activate the healthy immune system, it can also support prevention against SARS-CoV-2 infection; and its rational administration can also become a complementary therapy for COVID-19 and post-COVID-19 patients.
Conclusions and future perspectives
Covid19 what it is and how it works: it is currently a matter of great scientific, economic and medical interest. We at Erboristeria Como have tried to explain in a simple but detailed way all the immense work left to us by our molecular biologists until now. Also due to the unstoppable spread of new variants of the SARS-CoV-2 virus, research is always active to analyze new ways to weaken this virus, prevent its spread and even eliminate it. Among the latest scientific innovations are the scientific reports, available, regarding the biological properties of bromelain as a potential supportive treatment and prophylaxis of COVID-19 disease, which however require further in vivo tests. Research continues.
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