Coronavirus Treatments: What Drugs Might Work Against COVID-19?

Abstract

The World Health Organization declared the severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 virus outbreak as a pandemic on May 27, 2020. Since then, more than 5 488 825 cases across the world have been recorded at the time of revising this article. Governments around the world have imposed serious containment measures, meanwhile, the healthcare system is overburdened due to large increases in COVID-19 cases. However, no specific anti-SARS-CoV-2 virus drugs or vaccines have yet been shown to be effective to fight this causative virus of acute infectious pneumonia. The current review was conducted to look for potential natural and synthesized drugs for the treatment of COVID-19 patients. Previously published data in journals, textbooks, periodicals, websites, and sources, including data about the treatment of human coronavirus with natural and synthesized drugs, were taken from the online bibliographical databases. The results showed that syndic drugs approved for other human diseases have been used to improve the symptoms of patients infected with SARS-CoV-2. Several clinical trials across the world evidenced beneficial effects of natural and synthesized drugs in the treatment of SARS-CoV-2 infections. On the other hand, many studies have provided a deep understanding of the therapeutic effects of conventional and traditional medicine in identifying naturally occurring drugs effective against the SARS-CoV-2 virus. Both natural and synthesized drugs should come together to fight the SARS-CoV-2 virus and other potential emerging dangerous viral diseases since they have shown promising findings in clinical trials conducted with COVID-19 patients.

COVID-19, also known as 2019-nCoV and severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 virus, belongs to the family Coronaviridae. As SARS-CoV-2 belongs to the genus Betacoronavirus, it is closely related to MERS-CoV and SARS-CoV and thus is a positive-strand RNA virus with the largest viral genome of all RNA viruses which have been reported to cause severe symptoms of pneumonia in previous pandemics. ¹ The genetic structure of SARS-CoV-2 virus has been characterized and previously published. ^2,3 The main proteins in this virus and those previously identified in SARS-CoV and MERS-CoV showed a high similarity between them. Coronavirus infection is commonly induced by the virus rapidly integrating its genetic material into the host cell and multiplying, depending on the host organism for its development. ⁴

The first research on human coronaviruses (HCoVs) was carried out in the mid-1960s. ⁵ After 40 years a CoV was declared as the responsible agent for SARS, which caused a global health burden. ⁶ The novelty of this strain of virus means that many uncertainties are surrounding its behavior, and, therefore, it is too early to determine natural and synthetic drugs that could contribute to society as prophylactic agents or as suitable substances as anti-coronavirus drugs against COVID-19 virus. However, due to the high similarity between the COVID-19 virus and the previously reported SARS-CoV and MERS-CoV viruses, previously published research on natural compounds proven to exert anti-coronavirus effects may be a valuable guide to finding natural agents which may be active against the SARS-CoV-2 virus.

Currently, COVID-19 disease cases are growing very quickly worldwide. ⁷ In the United States, Brazil, Spain, Italy, and other countries, the COVID-19 pandemic is overburdening the healthcare system. ⁸ In real time, even though a series of potential drugs have been reported to improve the disease, there are no approved or recommended antiviral drugs for COVID-19.

To contribute to society as prophylactic agents against COVID-19, the current review was undertaken to look for the potential for the intervention of both synthetic and natural drugs to fight COVID-19.

Material and Methods

Data Collection

Previously published data in journals, textbooks, periodicals, websites reporting the treatment of coronavirus with conventional and traditional medicine were taken from the online bibliographical databases such as Google, Google Scholar, PubMed, Science Direct, and Springer Link. These data were searched using keywords related to natural and synthesized drugs used in coronavirus treatment. A list was established as a table including the medicinal plants declared to be used in the treatment of coronavirus around the world. The consulted sources were also searched for pharmacological studies giving supportive information on the detail of the involved plants such as the responsible compound classes as well as the mechanism of action.

Results and Discussion

Evidence of Conventional Treatment of Human Coronaviruses

Although there is active research to develop efficient drugs to fight COVID-19, no specific antiviral therapeutics have been developed, and the main adopted treatment strategy is a combination of antibiotics, antivirals, corticosteroids, and convalescent plasma from recovered patients. ⁹ COVID-19 patients have been treated with a combination of antibiotics and the HIV protease inhibitors ritonavir and lopinavir. ¹⁰ Ribavirin, an analog of ritonavir, ¹¹ may present promising efficacy on COVID-19 since this drug was used in the treatment of the respiratory syncytial virus. Moreover, ribavirin was approved for treating the SARS and MERS outbreak. ^{11 -13} However, earlier data reported that ribavirin induced severe secondary effects such as anemia; its efficacy on SARS-CoV-2 was also not clear. ¹² The RNA polymerase of RNA viruses, such as the influenza virus, may be inhibited by the nucleoside analog favipiravir. ¹⁴ Literature shows that it possessed an anti-SARS-CoV-2 effect, but its in vivo efficacy was elusive. Remdesivir could be a promising treatment for the treatment of COVID-19 patients. This drug showed in vitro and in vivo effects on an array of RNA viruses including SARS as well as MERS ¹⁵ and reduced viral loads sufficiently in treated animals. ¹⁶ As reported earlier, remdesivir had a significant effect on SARS-CoV-2 in Vero E6 cells, and patients affected by SARS-CoV-2 recovered after they received remdesivir intravenously. ^10,17 At present, remdesivir is under clinical trial assessment for COVID-19 patients. ¹⁸ Even though oseltamivir has been used to treat COVID-19 patients, its efficacy has not been confirmed. ¹⁰

Other drugs previously approved for the treatment of human diseases have been tested against SARS-CoV-2, which may lead to a potential treatment for COVID-19 patients. Chloroquine and hydroxychloroquine showed potential broad-spectrum antiviral effects on SARS-CoV-2, ¹⁹ and their efficacy is currently under clinical trials. Available data have recommended the use of IFNα atomization inhalation to treat COVID-19 patients, ⁹ and clinical trials have been conducted on the potential of IFNα-2b treatment of COVID-19 since it was approved to treat HCV infection. ²⁰ However, its efficacy has not been well shown. Earlier published data showed that corticosteroids were used to reduce the cytokine elevation in patients affected by SARS-CoV ²¹ as well as MERS-CoV. ^22,23 However, the effect on these patients was unclear, and the clearance of the viruses was delayed by the treatment with corticosteroids. ^24,25 Corticosteroids have not been recommended for systematic use in the treatment of COVID-19 patients.

Convalescent plasma could be a promising tool to fight COVID-19 since it significantly decreased the viral load in severe influenza and SARS-CoV patients and, therefore, reduced the mortality. ^24,26 COVID-19 patients treated with convalescent plasma in China showed promising results, although the efficacy needs further evaluation ¹⁶.

Medicinal Plants or Their Constituents for the Treatment of Coronavirus Infection

Since natural products have been used to treat infectious diseases for many years, there is potential for the intervention of such products for the complementary or alternative treatment of coronavirus infection. Literature from across the world has reported the history of the intervention of traditional medicine in the treatment of coronavirus infection that occurred in humans and animals. Plant products or their constituents could be a promising weapon for the treatment of COVID-19 since early patients with SARS-CoV infection have benefited from alternative medicine (Table 1).

Table 1

Medicinal Plants Used for the Treatments of Coronavirus Infection.

Plant name/family	a—Plant part b—Method of extraction c—Concentration	Mode of action	Year of study	Targeted virus	Reference
Sophora flavescens Ait. Fabaceae	a—Sophorae radix b—Methanolic extraction/sonication (3 h) c—Doses tested: 25, 50, 75, and 100 mg/mL of the extract	Decrease of intracellular viral RNA levels, MHV-A59, viral proteins production, and viral replication	2010	MHV-A59, PEDV	27
Sanguisorba officinalis L. Rosaceae	a—Sanguisorbae radix b—Methanolic extraction/sonication (3 h) c—Doses tested: 25, 50, 75, and 100 mg/mL of the extract	Decrease of coronavirus production and protein synthesis levels	2010	MHV-A59, PEDV	27
Acanthopanax gracilistylus W.W.Sm. Araliaceae	a—Dried root barks b—Methanolic extraction/sonication (3 h) c—Doses tested: 25, 50, 75, and 100 mg/mL of the extract	Induction of cyclooxygenase-2 expression via the activation of ERK and p38	2010	MHV-A59	27
Tylophora indica (Burm.f.) Merr. Apocynaceae	a—Leaves b—Methanol extract c—Concentrations tested: 30-1000 nM	Tylophorine compounds inhibited the TGEV-induced apoptosis and subsequent cytopathic effect in ST cells and blocked the TGEV replication	2010	TGEV	28
Cimicifuga racemosa (L.) Nutt. Ranunculaceae	a—Cimicifuga rhizoma b—No data c—No data	Decrease of PEDV levels and can have a potent anti-coronaviral effect	2020	PEDV	29
Melia azedarach L. Meliaceae	a—Meliae cortex b—No data c—No data	Decrease of PEDV levels and can have a potent anti-coronaviral effect	2020	PEDV	29
Coptis chinensis Franch Ranunculaceae	a—Coptidis rhizome b—No data c—No data	PEDV has a potent anti-coronaviral effect	2020	PEDV	29
Litchi chinensis Sonn. Sapindaceae	a—Seeds b—Flavonoids extract c—No data	Flavonoids extracted from the litchi seeds have an important effect on SARS-CoV3CL symptoms by inhibiting the proteinase activity which is essential for viral protein synthesis	2020	SARS-CoV3CL	29
Camellia japonica L. Theaceae	a—Flowers b—Oleanane triterpenes extract c—10, 8, 2, and 1 µM	Coumarins from Saposhnikovia divaricata, oleanane, triterpenes from Camellia japonica L., and phloroglucinols from Dryopteris crassirhizoma exerted potential inhibitory effects on PEDV replication by inhibition of viral replication	2016	PEDV	30
Saposhnikovia divaricata (Turcz.) Schischk. Apiaceae	a—Radix b—Coumarins extract c—10, 8, 2, and 1 µM		2016	PEDV	30
Dryopteris crassirhizoma Nakai Dryopteridaceae	a—Rhizomes b—Phloroglucinols c—10, 8, 2, and 1 µM		2016	PEDV	30
Scrophularia scorodonia L. Scrophulariaceae	a—No data b— Saikosaponins (A, B2, C, and D) c—Concentrations: 0, 2.5, 25, and 250 mmol/L	Saikosaponins (A, B2, C, and D) have anti-HCoV-229E activity and saikosaponin B2 possesses the strongest effect	2006	HCoV	31
Cimicifuga racemosa (L.) Nutt. Ranunculaceae	a—Rhizomes b—Methanolic extract/ultrasonic conditions c—concentration tested: 100 µg/mL	Reduction of the MHV production and the intracellular viral RNA, protein expression, and PEDV production	2008	MHV-A59, PEDV	32
Melia azedarach L. Meliaceae	a—Cortex b—Methanolic extract/ultrasonic conditions c—Concentration tested: 100 µg/mL		2008	MHV-A59, PEDV	32
Coptis chinensis Franch Ranunculaceae	a—Rhizomes b—Methanolic extract/ultrasonic conditions c—Concentration tested: 100 µg/mL		2008	MHV-A59, PEDV	32
Phellodendron chinense Schneid Rutaceae	a—Cortex b—Methanolic extract/ultrasonic conditions c—Concentration tested: 100 µg/mL		2008	MHV-A59, PEDV	32
Sophora subprostrata L. Fabaceae	a—Radix b—Methanolic extract/ultrasonic conditions c—Concentrations tested: 100 µg/mL		2008	MHV-A59, PEDV	32
Juniperus formosana Hayata Cupressaceae	a—Heartwood b— Abietane-type diterpenoids (isolated compound) c— Concentrations tested: 0.1-10 µM	Abietane-type diterpenoids possess important anti-SARS-CoV effects	2007	SARS-CoV	33
Chamaecyparis obtusa (Siebold & Zucc.) Endl. Cupressaceae	a—Heartwood b—Savinin (purified molecule) c— Concentrations tested: 0.1-10 µM	Savinin and betulinic acid are competitive inhibitors of SARS-CoV3CL protease	2007	SARS-CoV	33
Compounds from several medicinal plants	a—No data b— Apigenin-7-glucoside, catechin, luteolin-7-glucoside, demethoxycurcumin, oleuropein, epicatechin-gallate curcumin c—No data	Potent inhibitors of COVID-19 Mpro	2020	COVID-19	34
Euphorbia neriifolia L. Euphorbiaceae	a—Leaves b—Ethanolic extract c—No data	The triterpenoid 3β-friedelanol exerted the potent antiviral effect than the positive control (actinomycin D)	2012	HCoV	35
Isatis indigotica Fortune ex Lindl. Brassicaceae	a—Root b—Emodin and hesperetin (purified compounds) c—Concentrations tested: from 1 to 500 µg/mL	Hesperetin and aloe-emodin inhibited the cleavage activity of 3C-like protease (3CLpro) of SARS-CoV	2005	SARS-CoV	36
Galla chinensis L. Anacardiaceae	a—No data b—Tetra-O-galloyl-d-glucose c—Concentrations tested: 10-3 to 10-7 mol/L	Tetra-O-galloyl-d-glucose from Galla chinensis inhibits the entry process of SARS-CoV into host cells	2004	SARS-CoV	37
Veronica linariifolia Pall. ex Link Plantaginaceae	a—No data b—Luteolin c—Concentrations tested: 10-3 to 10-7 mol/L	Luteolin inhibits the SARS-CoV	2004	SARS-CoV	37
Morus alba L. Moraceae	a—No data b—No data c—Concentrations tested: 0-400 µg/mL	The herbal formula (KDBFD) transiently modulated the human immune system	2011	SARS-CoV	38
Chrysanthemum Morifolium Ramat. Asteraceae	a—No data b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Forsythia suspensa (Thunb.) Vahl Oleaceae	a—No data b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Platycodon grandiflorum (Jacq.) A. DC Campanulaceae	a—Radix b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Glycyrrhiza uralensis Fisch. ex DC. Fabaceae	a—Radix b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Scutellaria baicalensis Georgi Lamiaceae	a—Radix b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Saposhnikovia divaricata (Turcz. ex Ledeb.) Schischk. Apiaceae	a—Radix b—No data c—Concentrations tested: 0-400 µg/mL		2011	SARS-CoV	38
Houttuynia cordata Thunb Saururaceae	a—No data b—No data c—IC50 = 251.1 µg/mL	Immunostimulatory and antiviral effects	2011	SARS-CoV	38
Ganoderma lucidum (Curtis ex Fr.) P. Karst. Ganodermataceae	a—No data b—No data c—IC50 = 41.9 µg/mL	Ganoderma lucidum inhibited SARS-CoV RNA-dependent RNA polymerase	2011	SARS-CoV	38
Compounds from several medicinal plants	a—No data b—Flavonoids c—No data	Kaempferol glycosides are good candidates for 3a channel proteins of coronaviruses	2014	SARS-CoV	39
Rheum officinale Baill. Polygonaceae	a—Root tubers b—Ethanolic extract c—Concentrations 0.1-100 µg/mL	Emodin, an anthraquinone compound, blocked the binding of SARS-CoV S protein to ACE2 and the infectivity of S protein-pseudotyped retrovirus to Vero E6 cells	2007	SARS-CoV	40
Toona sinensis (Juss.) M. Roem. Meliaceae	a—Leaf b—Water extract c—Concentrations tested: 5, 20, 50, and 200 µg/mL	Tender leaf extract of Toona sinensis was found to have an important effect on SARS-CoV but the action mode of Toona sinensis Roem. to inhibit SARS-CoV remains unclear	2008	SARS-CoV	41
Rheum palmatum L. Polygonaceae	a—Rhizomes b—Alcoholic extract c—Concentrations tested: 100, 50, 25, 12.5, 6.25, 3.12, and 1.56 µg/mL	Rheum palmatum L. was found to inhibit 3 CL protease activity, as already known that the activity of 3C-like proteases is inhibited, SARS-CoV replication in the host cell will be also inhibited	2009	SARS-CoV	42
Compounds from several medicinal plants	a—No data b—Flavonoids c—Concentrations tested: 0.5-2.5 µM	Pectolinarin, rhoifolin, and herbacetin blocked the enzymatic activity of 3C-like protease and as a result SARS-CoV replication	2020	SARS-CoV	43
Compounds from several medicinal plants	a—No data b—Water extract c—Concentrations tested: 0-60 µM	Quercetin, epigallocatechin gallate, and gallocatechin gallate inhibited 3C-like protease of SARS-CoV (the 3C-like protease of a SARS-associated coronavirus (SARS‐CoV) is vital for SARS-CoV replication)	2012	SARS-CoV	44
Chromadex	a—No data b—No data c—Concentrations tested: 0.01, 0.1, 1, and 10 µM	Myricetin and scutellarein inhibited SARS-CoV helicase protein by affecting the ATPase activity	2012	SARS-CoV	45
Scutettaria baicalensis L. Lamiaceae	a—No data b—No data c—Concentrations tested: 0.01, 0.1, 1, and 10 µM		2012	SARS-CoV	45
Stephania tetrandra S. Moore Menispermaceae	a—No data b—No data c— Concentrations tested: 0.2, 1, and 5 µM	bis-Benzylisoquinoline alkaloids—tetrandrine, cepharanthine, and fangchinoline—suppressed the replication of HCoV-OC43 and inhibited viral S and N protein expression	2019	HCoV	46
Pyrrosia lingua (Thunb.) Farw. Polypodiaceae	a—Leaf b—Chloroform extract c—EC50 = 43.22 µg/mL	The herbal formula induced significant inhibition effects on SARS-CoV-induced cytopathic effect	2005	SARS-CoV	47
Artemisia annua L. Compositae	a—Whole plant b—Ethanolic extract c—EC50 = 34.52 µg/mL		2005	SARS-CoV	47
Lindera aggregata (Sims) Kosterm. Lauraceae	a—Root b—Ethanolic extract c—EC50 = 88.2 µg/mL		2005	SARS-CoV	47
Lycoris radiata Miq. Amaryllidaceae	a—Stem cortex b—Ethanolic extract c—EC50 = 2.4 µg/mL		2005	SARS-CoV	47
Cladastris lutea L. Fabaceae	a—No data b—Glucose c—Concentrations tested: 640, 256, 120, and 41 µg/mL		2007	SARS-CoV	47
Artocarpus integrifolia L. Moraceae	a—No data b—Galactose c—Concentrations tested: 640, 256, 120, and 41 µg/mL		2007	SARS-CoV	47
Phragmites australis (Cav.) Trin. ex Steud. Gramineae	a—No data b—N-acetyl glucosamine c—Concentrations tested: 640, 256, 120, and 41 µg/mL		2007	SARS-CoV	47

ERK, extracellular signal-related kinase; HCoV, human coronavirus; MHV-A59, mouse hepatitis virus A59; PEDV, porcine epidemic diarrheavirus; SARS-CoV, severe acute respiratory syndrome coronavirus; TGEV, transmissible gastroenteritis coronavirus.

Conclusion

The current review summarizes a range of natural and synthesized products that have been shown previously to have beneficial antiviral properties and may have potential as prophylactic agents against COVID-19. Further studies involving both traditional and conventional medicine may lead to identifying novel agents that could be promising weapons to fight COVID-19 or any other potential emerging dangerous viral diseases. The safety of traditional medicine in the treatment of COVID-19 patients has not been investigated in the current work, and, therefore, the toxicological assessment of any natural medicine would need to be meticulously evaluated. Any potential toxicity or interference of the product with either traditional or conventional medicine induced by herb-drug interaction should be understood.