Key words
antiviral drug - 2019 nCoV - curcumin - catechin - 1-piperoylpiperidine - ACE-2 inhibitor
Introduction
German veterinarians were puzzled in 1912, due to over the case of a feverish cat
with extreme superfluous abdomen. That was the first time reported paradigm power
of a coronavirus but veterinarians could not understand it at that time. It was few
decades, coronavirus was giving chickens bronchitis and pigs an intestinal disease
that killed almost every piglet under two weeks old and first time was identified
animal coronavirus in 1930. Until 1960s, these pathogens remained an obscure link
between animals and humans. In 1960, scientist’s United Kingdom and the United States
isolated two virus with corona like or crown like morphology were responsible for
causing common colds in humans. The name coronavirus coined in 1968 is derived due
to resemble the solar corona or crown like structure under electron microscope for
the entire group of this virus. The sequence of the killer virus may be as follows:
dog harms cats, the cat target pig intestines. The launching of severe acute respiratory
syndrome (SARS) in 2003 caused by a new virus which belonged to coronavirus family
had been playing role as a killer machine to kill the people and declared a pandemic,
earlier believed that coronavirus causes only mild symptoms in humans [1]. Nowadays a new version of coronavirus family was produced, a mutant may be by natural
phenomenon or manmade virus with high spread power death toll from the COVID-19 pandemic.
A 55 years old person from Hubei province could have been the first patient to have
infected with the virus on November 17, 2019 the first case of novel severe acute
respiratory syndrome emerged and then spread on the whole globe [2]. Doctor Jixian Zhang credited with first identifying the COVID-19 coronavirus has
defended the country's response to the outbreak in an interview with state television
on 27 December, amid international accusations that officials initially tried to conceal
the crisis. After isolation and identification this pathogen originally called 2019
novel corona virus (2019-nCoV) [3] but has subsequently been officially named severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) by the WHO. On 11th February, 2020 the WHO announced a name for the new coronavirus disease called as
COVID-19. On the same day, the coronavirus study group of the International Committee
on Taxonomy of Viruses named 2019-nCoV as severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2). As on February 2020 to 25 Sep. 2020, 32110656 confirmed cases 980011
deaths have been reported for COVID-19 globally [4] (comparative study at different time interval reported in [Fig. 1]). According to globally available data, COVID-19 caused by 2019-nCoV virus is the
killer machine [5]. Possible ways to Inhibition of transmission: As per discussion above and urgency of outbreak has led to the empiric use of broad-spectrum
antibiotics and antiviral agents some are clinically approved and some not approved
in affected patients in several countries. There are four general approaches to cure
and control this pandemic disease caused by the (SERS-COV-2) is as follows: 1. Direct
antiviral effects, 2. Inhibition of viral entry and replication at the cellular level
by targeting virus-related processes, 3. Enhancement of host immune response and 4.
Social distancing includes hygienic activities and complete lockdown [6]. At present time there are no antiviral agents of SARS-CoV-2 available. Scientists
have been facing a big challenge to find possible treatments to save life and discover
vaccines for future prevention of the virus, social distancing and complete lockdown
is the only way to slow down the transmission of virus. Social distancing and lockdown
is not an effective solution to kick off the virus and it is also not possible to
lockdown for long time and not feasible for mankind & economical aspects also. In
this view, our aim was to introduce an easy and fast way to cure and control the action
of aforesaid virus by triple action i. e. masking/inhibition of Spike protein receptor
binding domain (RBD) of Virus, ACE-2 receptor & TMPRSS-2 Co-enzyme of host cell against
to this pandemic disease using by ancient Ayurvedic remedy as soon as earlier along
with theoretical scientific approach without any failure in the respect of inhibition
of viral entry and replication at the cellular level by targeting virus-related processes
along with enhance of host immunity. We are strongly recommended a therapy to cure
and control the COVID-19, not for India but all over the globe in respect of mankind
as well as our golden future.
Fig. 1 Comparative study of total number of patients, total number of death, increase number
of patients and increase number of death at different time interval.
Ancient Ayurvedic Therapeutic Agents
Ancient Ayurvedic Therapeutic Agents
Curcuma Longa L. (Turmeric)
Indian tradition believe that turmeric is a divine plant given to human being by God.
Therefore, turmeric has always been a part of Vedic rituals in India. Sunlight dried
powder of Curcuma longa L (Indian name haldi) is the good source of Curcumin [7]. Curcumin and its derivatives are found as effective inhibitor of triple target
receptors to arrest the launch of SARs-COV-2, Angiotensin converting enzyme-2 (ACE-2),
TMPRSS2 receptors of host cells and Spike protein of virus. Curcumin and dimethoxy
curcumin potently inhibits the activity of amino peptidase N (APN) /CD13. Curcumin
has enough binding energy to each receptor and stronger inhibitory activities against
COVID-19. So, it can be used as potential therapeutic agent against COVID-19 patient
without adverse side effects.
Black pepper (Piper Nigrum)
Black pepper is used as medicine to treat digestive and respiratory tract related
diseases caused by viral infection like as acute respiratory infection, asthma, chronic
indigestion, and fever [8]. Black pepper is the good source of piperine (1-piperoylpiperidine), which is used
as oral supplement to increase plasma level of coenzyme Q10. Black pepper Increase
enzymatic activity, lipid per oxidation, antioxidant, bioavailability enhancer, immunomodulatory
effect, WBC count and inhibit a dipogenesis [9]. Due to bioavailability effects of piperine it increases the level of curcumin and
catechin in plasma and play a vital role to inhibit the entry of 2019-nCoV in cell.
Green Tea
Green tea contains a large number of compounds that is said to be beneficial to human
health as Catechins, Caffeine, Theanine, Vitamins (Vitamin C, Vitamin B2, Folic Acid, β-carotene, Vitamin E), Saponins, Fluorine, γ-amino butyric acid, Chlorophyll
etc. Catechins are a type of polyphenol and the main astringency component in green
tea, Catechin was first isolated from the Indian plant extract catechu. Catechin has
duly binding affinity i. e. Spike protein RBD of Virus and ACE-2 Receptor of target
cell. Catechin shows the potential inhibitory effect on COVID-19. Piperine component
of Black Pepper has shown the bioavailability enhancer effect and increase the catechin
concentration in tissues of the human body distribution with concomitant effect by
inhibiting glucuronidation and gastrointestinal transit. Hence, both of them in combine
form can be used as a potential drug against COVID-19 disease.
Recipe to Treat COVID-19
COVID-19 patient may be treated as following manner with ayurvedic recipe which will
be shown the promising results along with the fast recovery. This recipe will also
be beneficial for preventing the 2019-nCoV and to enhance the immune response.
Mixed 3 gm fresh turmeric paste with 0.5 gm fresh black pepper powder and equally
divided it in to 3 part, each part of freshly prepared ayurvedic medicine introduce
to patient orally with lukewarm cow milk thrice a day and 100 ml green tea twice a
day (boil 2 gm dry leaf of green tea along with 0.25 gm Black pepper in 100 ml water).
After introducing this dose to the patient, take 2.5 gm freshly prepared sun flower
seed powder mixed it with lukewarm cow milk and introduce to the COVID-19 patient
once a day. This aforesaid therapy will be promising results in respect of COVID-19
patient.
Mechanism of the Pathogen
Mechanism of the Pathogen
Coronaviruses (CoVs) are relatively large viruses containing a single-stranded positive-sense
RNA genome encapsulated within a nucleocapside protein and glycoprotein membrane envelope.
The coronavirus genomes encodes four types of structural proteins nucleocapsid protein,
membrane glycoprotein, envelope protein and spike protein in which spike protein is
a major functional inducer of host immune responses [10]. Severe Acute Respiratory Syndrome caused by coronavirus is covered by enveloped
spike glycoproteins (that give crown-like appearance) [11] essential for viral entry into the host cell that contains a variable receptor-binding
domain (RBD) [6]. The RBD of Coronavirus binds to angiotensin converting enzyme 2 (ACE-2) receptor
[12] and aminopeptidase N (APN) another known name is CD13, dipeptidyl peptidase 4 (DPP4)
[13]
[14], carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), Cellular serine
protease found in the heart, lungs, kidney and gastrointestinal tract thus facilitating
viral entry into the host cells [15]
[16]. The coronaviruses are also enveloped positive strand RNA virus with the largest
genomes of RNA viruses characterized by 3–4 envelop binding and subsequent membrane
fusion process of coronavirus are mediated by the spike membrane glycoprotein (Spike
protein). The S protein membrane contains three segments: a large ectodomain, a single
pass transmembrane anchor and a short intracellular tail [15]. The ectodomain is distinct functional receptor-binding domain near the sub-unit
Amino (S1 or N) and a membrane fusion sub-unit carboxy (S2 or C) terminal [17]. These spike function to define viral tropism by their receptor specificity S1 or
N terminal binds on the host cell surface by ACE-2 receptor for viral attachment and
perhaps also by their membrane fusion by S2 or C terminal subunit activity virus genomes
to enter into the host cell by the complex proteolytically processed by type-2 transmembrane
serine protease enzyme encoded by TMPRSS-2 gene leading to cleavage of ACE-2 and activation
of the Spike protein. Viral entry and cell infection trigger the host’s immune system
and the inflammatory cascade is initiated by antigen-presenting cells (APC). The process
starts with the ACP performing two functions: first is presenting the foreign antigen
to CD4+ T-helper cells and second one is releasing interleukin-12 to further stimulate
the T-helper cells. The T-helper cells stimulate CD8+ T-killer cells that will target
any cell containing the foreign antigens. In addition, activated T helper cells stimulate
beta cells to produce antigen-specific antibodies [18]
[19]
[20].
Concomitant Effects of Curcumin & Catechin with Piperine
Concomitant Effects of Curcumin & Catechin with Piperine
Curcumin has the poor absorption bioavailability due to rapid metabolism in liver
and small intestinal wall. The major component of the black pepper is the alkaloid
Piperine (1-pieroylpiperidine) enhance the bioavailability of the drugs by inhibition
of glucuronidation in the liver and small intestine. Concomitant administration of
turmeric powder with Piperine & Catechin with Piperine increase the absorption bioavailability
2000% with no adverse side effects [21]. Due to increase the bioavailability, it will play indefinable promising role to
cure and control the COVID-19 outbreak globally along with enhance the immune response.
Molecular Bonding
Ligand (curcumin or catechin) molecule linked to the site of ACE2 receptor which provides
the way to virus entry in host cell. Similarly it was also seen that ligand molecule
binds to the RDB animo acid (S protein) which involved in host cell binding. Carbon
hydrogen bond, conventional hydrogen bond and Van der waals force are formed between
Curcumin or Catechin (ligand) and S-protein (amino acid). It also proves that ligands
have strong bonding affinity with ACE-2 as well as S-protein but binding affinity
of catechin is more than curcumin. Hence curcumin and catechin create inhibition environment
between RBD and ACE-2 receptors which cause the virus to not enter in the host cell
([Fig. 2]).
Fig. 2 Binding representation, a binding of ACE2 with Curcumin, b binding of S-protein with Curcumin, c binding of ACE2 with Catechin, d binding of S-protein with Catechin.
The linkage of ACE-2 receptor and S-protein with ligand includes conventional H-bond,
Carban hydrogen bond, π―σ bond, π―alkyl bond and π―π interaction. Curcumin directly
bonded to ACE-2 receptor of host cell amino acids: ANS A:210, LYS A:94, LEU A:91,
ALA A:396, LYS A:562, ALA A:99, TYR A:196, GLY A:205, TYR A:207, GLU A:208, GLU A:564,
ASP A:206 (By Van der waals forces); GLN A:102, TRP A:566 (by conventional); GLN A:98
(C―H bond); VAL A:209, PRO A:565, VAL A:212 (π―alkyl bond); LEU A:95 (π―σ bond). Catechin
bonded to ACE-2 receptor of host cell amino acids: TRP A:349, SER A:44, ASP A:350,
GLY A:352, HIS A:378, ALA A:348, AGR A:514, TYR A:510, TYR A:50, ANS A:51, ANS A:63
(By Van der waals forces); SER A:43, ASP A:382 (by conventional H-bond); HIS A:401,
TRP A:69, SER A:47 (C―H bond); MET A:62, ARG A:393 (π―Alkyl bond); HIS A:401, PHE
A:390, PHE A:40 (π―π stacket linkage); HIS A:401, PHE A:390, PHE A:40 (π―π T shaped
linkage ). Curcumin directly linked with S-protein of 2019-nCoV amino acids: LEU C:546,
GLY C: 548, PHE C: 541, ANS A:856, LEU A:997, SER A:967, ASP C:571, ALA C:570, VAL
A:976, THR C:572 ( by Van der Waals forces); ASP A:979, THR C:547, AGR A:1000, SER
A:975 (by conventional H-bond); THR C:573, ASN A:978, CYS A:743 (by carbon-hydrogen
bond); LER A:966 (by π―sigma bond). Catechin linked to S-protein amino acids: GLN
B:314, GLU B:309, LYS B:310, GLY B:311, ILE B:664, LYS C:733, LEU C:861, ASP B:950,
GLY C:769, ALA C:766, LYS B:304, THR C:761 ( by Van der waals forces); TYR B:313,
THR C:768, ASN C:764, THR B:302, GLN B:954, ASP C:775 (by conventional H-bond); ILE
B:312 (by C―H bond); THR C:768, VAL C:772, LEU B:303 (π―σ bond); ARG C:765 (π―cation);
ILE B:312, PRO B:665, ARG C:765 (π―alkyl bond). Hydroxyl group of catechin has high
binding affinity to words the amini acid AGR-634 and VAL-635 of 2019-nCoV Spike protein.
In addition, these two polyphenols are strong immune boosters and have been reported
accounted for to initiate autophagy, another significant component of viral freedom
[22]
[23]
[24]. Along these lines, it is evident that transmission of viral disease can be stop
by using Curcuma Longa L, Green tea and Piper nigrum in daily life.
Intercalating of Piperine with Curcumin
Intercalating of Piperine with Curcumin
So as to survey the intercalating affinity of piperine with curcumin as a transporter
of the curcumin particle by way of metabolism, we have considered the idea of the
intermolecular complex. A low binding energy ―3.1 kcal/mol complex is formed by π―π
linkage between the benzene ring of curcumin and piperine ([Fig. 3]). As we find the distance between the enolic proton of curcumin to piperine to be
shorter than the phenolic proton of curcumin and piperine, we recommend that the essential
method of intercalation is through enolic intermolecular hydrogen holding and the
sandwich π―π linkage between the benzene rings of the curcumin and piperine molecules
[25]. On account of this these collaborations among piperine and curcumin compete for
intercalating between adjoining layers of curcumin thus providing for a channel for
piperine to bind to curcumin in supporting its transportation through metabolic pathways.
When glucuronosylation of curcumin is hindered by piperine, curcumin stays longer
time in the body and provide more time for the absorption of curcumin thus increase
the bioavailability of curcumin by 20-flod through this method.
Fig. 3 Intermolecular Complex formed by Curcumin and Piperine: The intermolecular distance
between carbonyl group of Piperine to Enol group, two phenolic hydroxyl groups of
Curcumin is 7.587Å, 9.688Å and 10.374Å, respectively.
Conclusion
COVID-19 pandemic has caused a severe blow to social life, health and economic status.
The malignancy of the virus can be detected only by the fact that it has killed many
millions of people so far. Hence, there is a need to curb COVID-19 comprehensively.
Our research suggest that the use of Curcuma Longa L (Curcumin), Piper Nigrum (Piperin)
and Green Tea (Catechin) in their daily lives regularly can cure and prevent COVID-19
outbreak and infection.
