Severe Acute Respiratory Syndrome Coronavirus-2 Emergence and Its Treatment with Alternative Medicines: A Review

 

Arif Nur Muhammad Ansori1, Viol Dhea Kharisma2,3, Amaq Fadholly1,

Martia Rani Tacharina4, Yulanda Antonius5*, Arli Aditya Parikesit6

1Doctoral Program in Veterinary Science, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

2Computational Virology and Complexity Science Research Unit, Division of Molecular Biology and Genetics, Generasi Biologi Indonesia Foundation, Gresik, Indonesia.

3Master Program in Biology, Department of Biology, Faculty of Mathematics and Natural Sciences,

Universitas Brawijaya, Malang, Indonesia.

4Department of Veterinary Microbiology, Faculty of Veterinary Medicine,

Universitas Airlangga, Surabaya, Indonesia.

5Department of Biology, Faculty of Biotechnology, University of Surabaya, Surabaya, Indonesia.

6Department of Bioinformatics, School of Life Sciences,

Indonesia International Institute for Life Sciences, Jakarta, Indonesia.

*Corresponding Author E-mail: yulandaantonius@staff.ubaya.ac.id

 

ABSTRACT:

Known as the causal factor of the recent global COVID-19 pandemic, any SARS-CoV-2 is not the only coronavirus that has constituted a menace to society and taken thousands of human lives. Two previous pandemics were also led by coronaviruses; such as the MERS-CoV in 2012 and another SARS-CoV in 2002. Only five months into existence, SARS-CoV-2 transmitted infection to approximately 75 million people and it has led to more than 1.5 million of deaths all over the world. Unfortunately, there has not been any specific treatment yet for COVID-19 yet and its control is purely empirical. The examinations of the parity between SARS-CoV-2 and SARS-CoV, in terms of their genomics, origin, epidemiology, and pathogenesis, suggested that we may use the previous data of MERS-CoV or SARS-CoV as a guideline for uncovering the effective approach to strive against SARS-CoV-2. Various studies have reported the positive effects of numerous phytochemical compounds against SARS-CoV and MERS-CoV. Interestingly, this idea has been emplyed for SARS-CoV-2, and in silico screening of phytochemical compounds has been performed for identifying the potential candidates for COVID-19 treatment. Curcumin is an example of a natural compound which was demonstrated as potent candidate contrary to SARS-CoV-2 protease derived from the in silico studies. Herein, the occurrence of SARS-CoV-2 and the aplication of alternative medicines for treating coronavirus diseases are briefly reviewed.

 

KEYWORDS: Alternative Medicines, Coronaviruses, COVID-19, SARS-CoV-2

 

 


INTRODUCTION:

Coronaviruses are fundamental pathogenic agents that cause respiratory, neurological, gastrointestinal, and systemic diseases in humans and animals1.

 

The name of “coronavirus” is derived from “corona,” which reflects the appearance of the spiky outer protein cover of the virus2. These viruses are acknowledged to be in the Coronaviridae family and included into the order Nidovirales that is segmented into four genera, which are Betacoronavirus, Deltacoronavirus Alphacoronavirus, and Gammacoronavirus3. Its genome comprises four genes that encode the structural proteins, such as the envelope, nucleocapsid, membrane, and S protein4 (Figure 1). Drew from the previous studies, they revealed that the S protein contributes a very compelling role in securing the receptors on the cell of the host. Consequently, the primary object for some therapies of antiviruses to cure MERS-CoV, SARS-CoV, and SARS-CoV-2 is this protein5.

 

Figure 1: Structure of SARS-CoV-2. S protein considered as the most fundamental protein located in the surface membrane of SARS-CoV-2 and other coronaviruses.

 

Indonesia is covered by various types of vegetation, including tropical rain forests6. Additionally, it is one of the top five countries in the world with a high diversity of plants7, with approximately 6,000 medicinal ones6. Consequently, such richness in medicinal plants has resulted in a long history of their use by the Indonesian population for curing several diseases8,9,10. Indeed, medicinal plants are used in many countries with natural diversity resources, beside Indonesia7.

 

Nowadays, in monitoring the newly appearing and reappearing viruses, any molecular epidemiology research has become an essential tool11,12. Furthermore, issued from both researches of Callaway13 and Shang et al.14, these have been concluded that various research groups globally have been developing vaccines for antiviral therapy to fight against SARS-CoV-2. Correspondingly, other prospective therapeutic alternatives have been addressed as well by Al-Tawfiq15 to remedy the COVID-19. He also expressed that during the in vitro assays, both remdesivir and chloroquine can be the alternatives as both considered to be demonstrative in impending SARS-CoV-2 effectually. Regardless of these encouraging medication alternatives, COVID-19 is still considered as a life-threatening illness with no any established effectual antiviral medication or confirmed vaccine yet.

 

Emergence of Sars-COV-2

The genera of Alphacoronavirus and Betacoronavirus proved that contaminate both animals and humans16,17,18 (Table 1), whereas Deltacoronavirus and Gammacoronavirus were merely infecting animals (Table 2), as gammacoronaviruses have been detected in whales and birds, whereas deltacoronaviruses have been isolated from birds and pigs17.

 

Table 1: Recognized human-infecting coronaviruses.

Alphacoronaviruses

Human coronavirus NL63

Human coronavirus 229E

Betacoronaviruses

SARS-CoV-2

MERS-CoV

SARS-CoV

Human coronavirus OC43

Human coronavirus HKU1

 

Table 2: Recognized Animal-infecting Coronaviruses.

Alphacoronaviruses

 

Porcine respiratory coronavirus

Feline infectious peritonitis virus

Transmissible gastroenteritis coronavirus

Rousettus bat coronavirus HKU10

Hipposideros bat coronavirus HKU10

Scotophilus bat coronavirus 512

Myotis bat coronavirus HKU6

Porcine epidemic diarrhea virus

Rhinolophus bat coronavirus HKU2

Miniopterus bat coronavirus 1B

Miniopterus bat coronavirus 1A

Miniopterus bat coronavirus HKU8

Miniopterus bat coronavirus HKU7

Betacoronaviruses

β-CoV A

Dromedary camel coronavirus UAE HKU23

Porcine hemagglutinating encephalomyelitis virus

E coronavirus

B coronavirus

Antelope coronavirus

Rabbit coronavirus HKU14

Murine coronavirus

Rat coronavirus Parker

β-CoV B

SARS-related palm civet coronavirus

SARS-related Rhinolophus bat coronavirus HKU3

β-CoV C

KSA-Camel-363

Pipistrellus bat coronavirus HKU5

Tylonycteris bat coronavirus HKU4

Neo coronavirus

MERS-CoV

Erinaceous coronavirus

β-CoV D

Rousettus bat coronavirus

Gammacoronaviruses

 

Beluga whale coronavirus SW1

Bottlenose dolphin coronavirus HKU22

Turkey coronavirus

Avian infectious bronchitis virus peafowl

Avian infectious bronchitis virus partridge

Deltacoronaviruses

 

Bulbul coronavirus HKU11

Thrush coronavirus HKU12

Munia coronavirus HKU13

Porcine coronavirus HKU15

White-eye coronavirus HKU16

Sparrow coronavirus HKU17

Magpie-robin coronavirus HKU18

Night-heron coronavirus HKU19

Wigeon coronavirus HKU20

Common-moorhen coronavirus HKU21

Historically, the first coronavirus was discovered in the early 1930s as a pathogen in the respiratory system of domesticated chickens1,2. In 2002, coronaviruses gained global attention with the emergence of SARS-CoV, which led to a worldwide epidemic that was notable for the thousands of deaths caused. In addition, MERS occurred in 2012, albeit with a lower mortality rate than that of SARS3. Epidemics are a part of history. SARS was the first indication that a coronavirus could be the series of life-threatening risks to human health. The emergence of SARS-CoV was a game-changing event that led to numerous studies, whereupon it was found to be the outcome of a cross-species transmission event from bats to humans17 (Figure 2).

 

Figure 2: Bats are accounted as a host with a supply of sources for several viruses, which drive some crucial diseases in animals and humans.

 

Since the surged prevalence of SARS-CoV, various animal-borne coronaviruses have been mutating and making the leap to humans to cause severe infections. Four more such coronaviruses have been recognized: the human coronaviruses HKU-1 and NL63, which cause mild respiratory diseases, and SARS-CoV-2 and MERS-CoV1,2. All seven coronaviruses that cause human diseases (Table 1) have crossed the species barrier, as the progenitor viruses of these strains were found in different host animals. HCoV-HKU1 and HCoV-OC43 are believed to be originated from rodents, whereas SARS-CoV, HCoV-229E, MERS-CoV, and HCoV-NL63 are widely acknowledge to be derived from bats3,19,20. Additionally, it is possible that domesticated animals can act as in-between hosts and entitle any transfer of the virus from their natural environments to humans. The intermediate hosts are postulated to be civets for SARS-CoV3,21,22, camelids for HCoV-229E, and dromedary camels for MERS-CoV3,23. SARS-CoV-2, the most recently identified coronavirus strain, was first in December 2019 detected in the City of Wuhan, China. It shares genomic resemblance with SARS-CoV and is postulated to have been transmitted to humans by animals in the live wild (sometimes endangered) animal markets in China. There are two most likely presumptions of its origin which are that pangolins or bats11,12,24,25 and accounted as the natural host. Bats are being the most distinctly expected and the virus then has the tendency of being mutated and transfers to humans through an intermediate animal as the in-between host. Currently, it is known that human-to-human transmission of SARS-CoV-2 does occur.

Previous study published the molecular phylogenetic analysis in S protein gene-based isolates of SARS-CoV-2 from diverse countries and other coronaviruses derived from bats, pangolins and, finally, humans (Figure 3)26. That study significantly established the first three submissions of Indonesian SARS-CoV-2 isolates from database (GISAID EpiCoV™). Moreover, it also uncovered that the S protein gene among the Indonesia isolated viruses had no any major dissimilarity4. On the other hand, according to Andersen et al.24, SARS-CoV-2 determinately showed that it was not a manipulated virus or a laboratory constructed virus. Additionally, Lam et al.27 expressed that coronaviruses are existing in many undomesticated mammals across Asia. It is very fundamental to make inquiries on the possible intermediate hosts of SARS-CoV-2 which spread the COVID-19. The genome of pangolin coronavirus is 91.02% indistinguishable from SARS-CoV-2 at whole-genome degree. Furthermore, Zhou et al.28 stated that the whole genome of SARS-CoV-2 shared 96% uniformity to any genome in a bat coronavirus strain isolated from Rhinolophus affinis (BatCoV RaTG13) which was collected from Yunnan, China. Based on the same previous study, this study encourages further monitoring studies on pangolins and bats from their natural environment, specifically the ones from Southeast Asia (including Indonesia), so that another risk of zoonotic transmissions could be anticipated.

 

Figure 3: Phylogenetic analysis showing the relatedness of SARS-CoV-2 isolates from patients in Indonesia to other coronaviruses from different countries26.

Alternative Medicines:

In the wake of the emergence of the coronaviruses, plants have proven as a resource of active compounds with various bioactivities and it has been recently used for drug development. Since antiquity, the Ebers Papyrus (an ancient Egyptian medical text), texts on traditional Chinese medicines, and Indian Ayurveda have provided descriptions of various medicinal plants that are used worldwide with various health benefit. Several phytochemicals exhibit functions such as immune-boosting, antibacterial, antifungal, and antiviral effects. Many plants generated compounds interrupt the various functional proteins of coronaviruses and thus can be used for the development of drugs against them. Since the whole-genome order of SARS-CoV-2 has immense parity with that of MERS-CoV and SARS-CoV, natural compounds with anti-MERS-CoV or anti-SARS-CoV activities may be an advantageous directory for discovering any effective anti-SARS-CoV-2 medicinal vegetations (Table 3).


 

Table 3: Plant Products with effects countering various human-infecting coronaviruses.

Virus

Plant/Plant Products

Action

References

MERS-CoV

Isobavachalcone, herbacetin, helichrysetin, quercetin, and 3-β-d glucoside

Inhibit SARS-3CLpro cleavage activity

29, 30

SARS-CoV

Rauwolfia spp.

Inhibit SARS-CoV replication

31, 32

Various flavonoids (quercetin, gallocatechin gallate, and epigallocatechin gallate)

Inhibit SARS-3CLpro activity

29, 33, 34, 35

Isatis indigotica

Inhibits SARS-3CLpro enzyme activity

36, 37

Rheum palmatum

Inhibits SARS-3CLpro activity

29, 38

Houttuynia cordata

Inhibits SARS-3CLpro activity and blocks viral RNA-dependent RNA polymerase activity

29, 39, 40

Myricetin and scutellarein

Inhibit nsP13 helicase activity

29, 41

Scutellaria baicalensis

Inhibits angiotensin-converting enzyme activity

29, 42, 43

Aesculus hippocastanum

Unclear

31, 44

Mannose-specific plant lectins derived from Hippeastrum hybrid, Galanthus nivalis, and Allium porrum

Inhibit the early stage of virus replication

31, 45, 46

Polygonum and Rheum

Inhibit the binding of SARS-CoV S protein with angiotensin-converting enzyme 2

29, 47, 48

Panax ginseng

Unclear

32

Glycyrrhizin from licorice roots

Various cellular pathways

31, 49, 50

Veronicalina riifolia

Interrupts SARS-CoV membrane fusion

29, 51

Ecklonia cava

Inhibits SARS-3CLpro activity

52

Torreya nucifera

Inhibits SARS-3CLpro activity

53

Toona sinensis

Inhibits the cellular entry of coronaviruses

29, 54

Lycoris radiata

Unclear

55

Galla chinensis

Interrupts SARS-CoV membrane fusion

29, 51

Kaempferol derivatives

Interferes with the ion channel activity of the SARS-CoV 3a protein

29, 56

 

 

Coronaviruses encode numerous proteins, of which some are fundamental for reproduction and viral entry into the cell of the host, for example, papain-like protease, S protein, and 3CLpro. Those have been relatively well investigated and considered as an important target for drug development4. Narges and Neda57 carried out the in-silico screening of various herbal plants to find the prospective preventions of SARS-CoV-2 proteases, which could be important in the fight against the virus. The robust dynamics of several phytochemical combinations with well-preserved regions that have the precise enzymatic interactions produced a low adverse effect. Therefore, natural compounds are considered as an effective and attractive antiviral drug. For example, curcumin has demonstrated a strong inhibitory effect on SARS-CoV-2 protease58 (Figure 4). Another study has demonstrated the advantages of in silico screening method for identifying the Chinese herbal medicines with effects countering SARS-CoV-2. By highlighting the speed of the method, low experimental costs, and low requirement for human trials, those accelerated the drug development59. One of the interesting developments is the utilization of nanoparticles conjugate with the natural products compound as an antiviral inhibitor60. It was found that several type of metals such as silver (Ag), selenium (Se), and gold (Au) elicited the antiviral activities61. The effort in creating conjugates of metals and natural products as inhibitor for SARS-CoV-2 provides an alternative solution for robust drug design and delivery system to the cells. This approach is worth trying as the metal-based nanoparticles have successfully elicited inhibition to various type of virus such as HIV, herpes, and hepatitis62. Moreover, various nanoparticle types have been successfully developed to inhibit SARS and MERS, the other types of coronaviruses63.

 

Figure 4: Curcumin, isolated from turmeric, as a potential remedial agent countering SARS-CoV-2 according to molecular docking method. This figure created in BioRender.

In the meantime, several existing allopathic drugs that might ameliorate degeneration of the clinical state and generate faster relief are also being tested. Some of the drugs which have been administered to patients are interferon-beta, chloroquine/hydroxychloroquine, lopinavir, and remdesivir. The convalescent plasma therapy is also being tested64. However, since those drugs have tendencies for generating severe side effects, their use in critical ill patients is limited65 (Table 4).

 

Table 4: Allopathic medicines used to treat COVID-19.

Drug

Use

Side Effects

References

Interferon-beta

Multiple sclerosis

Muscle aches, fever, pain, headache, nausea, and diarrhea

66

Chloroquine / hydroxychloroquine

Malaria

Abdominal cramps, idiosyncratic adverse drug reactions, nausea, cardiovascular effects, anorexia, hematological effects, retinal toxicity, diarrhea, vomiting, hypoglycemia, and neuropsychiatric and central nervous system effects

64, 67

Lopinavir

Human immunodeficiency virus (HIV)

Hepatotoxicity, gastrointestinal intolerance, cardiac conduction abnormalities, and pancreatitis

64, 68

Remdesivir

Ebola virus

Kidney problems

64, 69

 


CONCLUSION:

Despite the fact that the ancient traditional medicines lack standardization and validation, the high demand for alternative medicines has led numerous studies and clinical trials to prove their efficacy and safety. With the COVID-19 pandemic and the ineffectiveness of modern medicine to remedy the disease quickly, attention has been turned into traditional medicinal plants as a potential therapeutic alternative. Various studies on traditional medicinal plants are currently in progress to find the candidate from phytochemical compounds with prospective effects countering SARS-CoV-2. Traditional medicines may well prove invaluable, not only for the treatment of COVID-19 but also for the newly appearing and reappearing infectious illness, such as Zika, SARS, MERS and Ebola.

 

ACKNOWLEDGEMENT:

This study was fully reinforced by the Ministry of Education and Culture of the Republic of Indonesia. We thank Editage for improving the manuscript.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 12.11.2020            Modified on 02.12.2020

Accepted on 29.12.2020           © RJPT All right reserved

Research J. Pharm. and Tech 2021; 14(10):5551-5557.

DOI: 10.52711/0974-360X.2021.00967