ISSN: 0973-7510

E-ISSN: 2581-690X

Review Article | Open Access
Shubhangi Goel1 and Anjana Goel2
1King George’s Medical University, Lucknow – 226 001, Uttar Pradesh India.
2GLA University, Mathura – 281 406, Uttar Pradesh, India.
J Pure Appl Microbiol. 2020;14(suppl 1):841-848 | Article Number: 6233
Received: 22/04/2020 | Accepted: 13/05/2020 | Published: 22/05/2020
Abstract

The current global health emergency, COVID-19, is not the first time that coronaviruses have posed a threat to human world shrinking our numbers by thousands. Before this SARS-CoV in 2003 and MERS-CoV in 2013 have caused epidemics. Four months in existence, and it has already affected 1,995,983 people and taken over 131,037 lives worldwide, yet we do not have any specific treatment available with us and the management is purely empirical. Looking at the similarities between SARS-CoV and SARS-CoV-2 in origin, genomics, pathogenesis and epidemiology, we can bring the researches done for SARS-CoV in use which can be our guide in finding an effective management strategy against SARS-CoV-2. There are various researches and studies reporting the use and effect of various phytochemical compounds in SARS-CoV treatment. Already, the thought has been put into action and in-silico screening for various natural plant compounds have been done to find a potential candidate compound. One such example is of curcumin, a secondary metabolite of turmeric, which is found to be effective against COVID-19 protease by molecular docking analysis.

Keywords

Coronavirus, SARS-CoV, Herbal medicine, Complementary medicine

Introduction

Coronaviruses are well known pathogenic organisms of humans and animals which cause a broad spectrum of respiratory, gastrointestinal, neurological and systemic diseases1.

Deriving its name from the word ‘corona’2 meaning outer fringe(because of the presence of spiky outer enveloped protein coat), coronaviruses belong to the family Coronaviridae which are further subdivided into four genera namely, Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus3.

Table (1):
Recognised strains of Coronavirus affecting humans.

Alphacorona virus
HCoV- 229E
HCoV-NL63
Betacorona virus
HCoV-OC43
 
HCoV-HKU1
 
SARS-CoV
 
MERS-CoV
 
SARS-CoV-2

 

Evolution of Covid-19
The genera Alphacoronaviruses and Betacoronaviruses contain viruses infecting both humans and animals (Table 1)4,5 while the genus Gammacoronavirus and Deltacoronavirus contains viruses specifically infecting animals (Table 2)4; the first one being seen in whales and birds, and the latter ones are isolated from pigs and birds4.

Table (2):
Recognised strains of Coronavirus affecting animals.

Alphacorona virus
Mi-BatCoV-HKU7
 
Mi-BatCoV-HKU8
 
Mi-BatCoV-1A
 
Mi-BatCoV-1B
 
Rh-BatCoV-HKU2
 
PEDV
 
My-BatCoV-HKU6
 
Sc-BatCoV-512
 
Hi-BatCoV-HKU10
 
Ro-BatCov-HKU10
 
TGEV
 
FIPV
 
PRCV
Betacorona virus
β-CoV A
RCoV Parker
 
MHV
 
RbCoV HKU14
 
Antelope CoV
 
B CoV
 
E CoV
 
PHEV
 
DcCoV-UAE-HKU23
β-CoV B
SARSr-Rh batCoV-HKU3
 
SARSr-CiCoV
β-CoV C
Erinaceous CoV
 
MERS-CoV
 
Neo-CoV
 
Ty-batCoV-HKU4
 
Pi-BatCoV-HKU5
 
KSA-Camel-363
β-CoV D
Ro-Bat-CoV-HKU9
γ-CoV
IBV-partridge
 
TCoV
 
IBV-peafowl
 
BdCoV-HKU22
 
BWCoV-SW1
δ-CoV
NHCoV HKU19
 
WiCoV HKU20
 
CmCoV HKU21
 
MunCoV HKU13
 
MRCoV HKU18
 
PorCoV HKU15
 
SpCoV HKU17
 
WECoV HKU16
 
ThCoV HKU12
 
BuCoV HKU11

 

Discovered in early 1930’s as a pathogen causing mild respiratory infection in domesticated chickens1 coronaviruses gained major attention in 2003 after the emergence of SARS(Severe Acute Respiratory Virus) which caused a major global epidemic wiping out thousands of global population.

Before 2003 epidemic was inked in the history of humankind, coronaviruses were known to cause mild respiratory infections. It was the first time, when coronaviruses were seen posing such a serious threat. This was a game-changing event which led to various researches. As reported, SARS was known to be caused by cross species transmission- from bats to humans.

Since then, coronaviruses are seemingly undergoing variety of mutations and leaping into humans causing infections, both mild and severe. After SARS, four more strains of coronaviruses have been recognised till now of which two strains namely, HCoV HKU-1 and NL63 are known to cause mild respiratory disease while two strains namely, MERS-CoV and SARS-CoV-2 have caused epidemics affecting human population in large numbers and severity1. All the seven strains of coronaviruses recognised in humans are known to jump to humans from animals crossing species barrier (Fig. 1). The progenitor viruses of the recognised strains are seen in different host animals. HCoV- NL63, HCoV-229E, MERS- CoV and SARS- CoV are considered to have their origin in bats while HCoV-HKU1 and HCoV-OC43 are most likely to be originated from rodents3,6,7. Domesticated animals may play important roles as intermediate hosts which enable transmission of these viruses from their natural hosts to humans. SARS-CoV finds its intermediate hosts in civets3,8,9, HCoV-229E in camelids while MERS-CoV most likely found its way to humans through dromedary camels3,10.

Fig. 1. Evolution of various strains of recognised human coronavirus from natural to human host

The latest recently recognised strain of all, SARS-CoV-2, was recognised in December 2019, in Wuhan city of China. Seeing its genomic similarity with SARS-CoV, it is thought to have paved its way to humans from animals through the live animal markets of China. The two probable theories of the origin of the virus gives bats11-13 or pangolins13, 4 as the natural host of the virus, bats being the most closest. The virus, likely, then mutated and evolved to spread most probably though an intermediate animal bridge to humans and now human to human transmission can be easily noted.

Being of the common origin as of SARS-CoV, it was hypothesized that the virulence of SARS-CoV-2 will also be affected by the increasing temperatures especially above 39°C (same as in case of SARS-CoV). According to the various studies conducted in this regard, the result remains inconclusive. According to a study conducted in China, COVID-19 mortality decreased with increase in ambient temperature (above 39°C) along with increased absolute humidity15. A study conducted by Wang et al.16 showed reduction in transmission of the disease while studies conducted by Ye Tao et al.17 and Zhu et al.18 showed ambient temperature had no effect on the transmission of SARS-CoV-2.

Complementary Medicine
Since the emergence of human race, plants have been the source of countless compounds having medicinal properties and lead to drug discovery. Since the ancient times, Indian Ayurveda, Traditional Chinese Medicine Literature, ancient Egyptian Ebers Papyrus all gives description of various plants and herbs having medicinal properties which are even today used all over the world for various health benefits. Different plant compounds act as immune boosters and can act as antibacterials, antivirals as well as antifungals. The coronaviruses encodes various proteins which enables its functioning. Many plants produce compounds interfere with these proteins and can become a target for drug development. Since the gene sequence of COVID-19 has very high similarities between the man proteins of COVID-19 and in SARS or MERS, thus previously reported anti-SARS or anti-MERS natural compounds may become a valuable guide to find the affective anti-COVID-19 herbal plants (Table 3).

Table (3):
Plant products effective against various strains of Human Coronavirus.

Virus
Plant/Plant Product
Mode of Action
Reference
SARS-CoV
Phenolic plant compounds and  Extract of roots of Isatis indigotica
Inhibits SARS-3CLpro enzyme activity
[28,29]
Flavanoid Baicalin from Scutellaria baicalensis
Inhibits Angiotensin Converting Enzyme
[30,31,32]
Water extract of Houttuynia cordata
Inhibit the activity of viral SARS-3CLpro Block viral RNA-dependent RNA polymerase activity
[32,33,34]
Glycyrhizzin from the liquorice roots
Affects various cellular signalling pathways
[35,36,37]
Mannose-specific plant lectins derived from Galanthus nivalis ,Hippeastrum hybrid and Allium porrum
Inhibition of virus replication at an early stage by blocking S- receptor interaction
[35, 38, 39]
Reserpine derived from various species of Rauwolfia
Inhibits replication of SARS-CoV
[35, 40]
Scutellarein and myricetin
Inhibit nsP13 helicase by affecting the ATPase activity
[32,41]
Escin from horsechestnut
[35, 42]
Extracts of Rheum palmatum
Inhibit SARS-3CLpro activity
[32, 43]
Flavonoids (herbacetin, pectolinarin, epigallocatechin gallate, rhoifolin,quercetin, and gallocatechin gallate)
Inhibit SARS-3CLpro activity
[32,44, 45, 46]
Quercetin and TSL-1 from leaves of Toona sinensis Roem
Inhibit the cellular entry of SARS-CoV
[32, 47]
Emodin derived from genus Rheum and Polygonum
Inhibits interaction of SARS-CoV spike protein and ACE2
Blocks 3a ion channel inhibiting SARS-CoV triggered apoptosis
[32, 48, 49]
Tetra-O-galloyl-β-D-glucose from Galla chinensis
Binds with surface spike protein thus interrupting with membrane fusion of SARS-CoV
[32, 50]
Luteolin from Veronicalina riifolia
Binds with surface spike protein thus interrupting with membrane fusion of SARS-CoV
[32, 50]
Lycorine extracted from Lycoris radiate
Unclear
[51]
Ginsenoside-Rb1 from Panax ginseng
[40]
Biflavonoids(Amentoflavone, apigenin,quercetin,luteolin) from Torreya nucifera
Inhibits SARS-CoV 3CL pro activity
[52]
Kaempferol derivatives
Interfers with 3a ion channel of SARS CoV
[32, 53]
Dieckol from edible brown algae Ecklonia cava
Inhibits SARS-CoV 3CLpro activity
[54]
MERS-CoV
Herbacetin, quercetin, isobavaschalcone, 3-β-D glucoside and helichrysetin
Inhibits cleavage activity of 3CLpro enzyme
[32, 55]
HCoV-229E
Saikosaponins A,B2,C,D
(from Bupleurum spp.,
Heteromorpha spp., Scrophularia scorodonia)
Inhibits viral attachment and penetration at an early stage(saikosaponin B2)
[29, 56]
HCoV-OC43
Tetrandrine, fangchinolif ne, and cepharanthine
Inhibit the expression of HCoV- OC43 spike and nucleocapsid protein. Immunomodulation
[32,57, 58]
Emodin derived from genus Rheum and Polygonum
Blocks 3a ion channel inhibiting HCoV-OC43 triggered apoptosis
[32,49, 49]

There are more than a dozen of proteins which are encoded by coronavirus. Some of these proteins are essential to viral entry and replication. Papain-like protease (PLpro), 3C-like protease (3CLpro) and spike protein are the well studied proteins so far. All of these three proteins make attractive targets for drug development. Some of the herbal plants have been screened in silico by Narges & Neda 2020 to find the inhibitors for COVID-19 proteases, which could be an effective strategy for combating against this deadly virus. Due to the strong interaction of these natural compounds with enzymatically conserved regions and specific functionality, these compounds can be considered as effective antiviral drugs due to their natural origin and less likely to produce adverse effects if they enhance the interaction. Out of the eight tested secondary compounds curcumin was found to have strong interaction with protease of COVID- 1919. In another studies in silico screening with AI has been performed. It is a very fast method of screening reducing the cost of experiment as well as few human trials are required which leads to a fast development of drug20.

Until now, many existing allopathic drugs are also being tried continuously which may prevent worsening of the clinical condition of the patient and provide them early relief. Some of them being given to the patients include remdesivir, lopinavir, chloroquine or hydroxychloroquine and interferon beta-1a. Recently, convalescent plasma therapy is being tried21. But all these medicines have many potentially serious side effects thus limiting their use to critical patients only. Moreover, the efficacy of these medicines has not yet been proven and thus are restricted to compassionate use only22 (Table 4).

Table (4):
Commonly used Allopathic Medicines in COVID-19.

Drug
Initial Use
Mechanism of Action
Side Effects
References
Remdesivir
Ebola virus
Inhibits viral RNA polymerase
Kidney injury
[21, 23,59]
Lopinavir
Anti HIV
Acts against viral 3CL protease
Gastrointestinal intolerance, Pancreatitis,  cardiac conduction abnormalities, hepatotoxicity
[21,23, 60]
Chloroquine
Antimalarial
Decrease Lysosomal autophagy preventing entry of virus
Abdominal cramps,anorexia, diarrhea,nausea, vomiting.  Cardiovascular effects (QTc prolongation), hematologic effects (including hemolysis with G6PD deficiency), hypoglycemia, retinal toxicity, neuropsychiatric and central nervous system effects, idiosyncratic adverse drug reactions
[21, 23, 61]
Interferon beta-1a
Treatment of Multiple Sclerosis
Interfere with viral replication and up regulates CD73 in pulmonary endothelial cells
injection site reactions, flu-like symptoms, headache, muscle aches, nausea, pain, fever, diarrhea, infections.
[23, 62]

Randomised Control Trials are continuously being done to see and prove the efficacy of these drugs and to find an appropriate effective treatment. One of the biggest international clinical trials is being conducted by WHO which has been given the name “Solidarity”. Seeing the urgency of the need of an effective treatment against the COVID-19, this trial is said to reduce the normal time taken by 80%. Four regimens are currently included namely, remdesivir, lopinavir with ritonavir, chloroquine or hydroxychloroquine and lopinavir with ritonavir with interferon beta-1a23.

Although same is the case with complementary medicine and their use is dependent upon their recorded effects in the treatment of SARS and MERS and upon the various small clinical trials and that their efficacy against COVID-19 is not yet proven, but the lack of potentially serious side effects gives us a possible and much needed window for their use in the treatment of COVID-19 not only in critical patients but also in patients with mild clinical disease. Although complementary medicine cannot replace modern medicine but can act as its supplementary. The integrated treatment can be clinically more effective and decrease the suffering of the patient in both time and severity. National Health Commission of the People’s Republic of China, on Feb 17, reported that 60,107 confirmed COVID-19 patients were successfully treated with integration of Western medicine and Traditional Chinese Medicine24,25. Also, traditional pool can be exploited as a prophylactic medicinal source against the disease especially in high risk population by boosting up immunity, blocking the infection, cutting off the inflammatory storm and promoting repair of the body24.

CONCLUSION

Although modern medicine came over traditional medicine in Darwinian process especially in developed countries, it is still being used widely by much of the population especially in developing countries. In fact, the trend is continuously growing towards the use of traditional medicine which is now no longer “the poor man’s alternative to conventional care”26. Although the ancient traditional medicine seriously lacks validation and standardization27, but the increasing tilt of the society towards the alternative medicine source due to widespread increasing rate of chronic diseases as well as lack of modern allopathic medicine in treating various infectious diseases due to antimicrobial resistance, has lead to various researches and studies which proves their efficacy and safety in various advanced clinical trials. Lately, when the world is under attack by COVID-19 and where modern medicine is incapable of saving us our heads turn towards the traditional medicinal source to be our shield. A lot of researches are being done to find the potential candidates from the conventional herbal pool which can prevent the spread and stop the effect of the virus.

In view of such newly emerging and re-emerging infectious diseases such as Ebola virus, Nipah virus, Zika virus, COVID-19, having potential to cause epidemics and thus seriously affect the human race not only in severity but also in numbers, traditional medicine can lend us a way out which, as quoted by WHO, is the care that is close to homes, generally available, accessible, affordable and sometimes the only care available to people at primary health care level26.

Declarations

ACKNOWLEDGMENTS
Not applicable.

CONFLICT OF INTEREST
The authors declares that there is no conflict of interest.

AUTHORS’ CONTRIBUTION
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

FUNDING
None.

ETHICS STATEMENT
Not applicable.

AVAILABILITY OF DATA
All datasets generated or analyzed during this study are included in the manuscript and/or the Supplementary Files.

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