Antimalarial drugs from plant sources and cure for COVID-19

Interestingly, three drugs from plant sources have shown promise in treating viral infections including the novel coronavirus (COVID-19) and Human Immuno-deficiency Virus (HIV).

In recent decades, drugs used to treat malaria infection have been shown to be beneficial for many other diseases, including viral infections. In particular, they have received special attention due to the lack of effective antiviral drugs against new emerging viruses (that is, HIV, dengue virus, chikungunya virus, Ebola virus, coronavirus) or against classic infections due to drug-resistant viral strains (that is, human cytomegalovirus).

In fact, a study published this month in the journal Microorganisms concluded: “…Based on these observations, we can state that the use of antimalarial drugs might be useful, especially in cases of antiviral resistance and in light of the emergence of many viruses against which effective drugs are not available.”

The study is titled “The Use of Antimalarial Drugs against Viral Infection.”

Some of the antimalarial drugs shown to be effective against viruses include chloroquine derived from the bark of Cinchona tree; artemisinin from the Chinese salad plant (Artemisia annua); and neem tree (Azadirachta indica/dogonyaro in Hausa).

Chloroquine is a synthetic form of quinine, a compound found in the bark of cinchona trees native to Peru and used for centuries to treat malaria.

Chloroquine was an essential element of mass drug administration campaigns to combat malaria throughout the second half of the 20th century and remains one of the World Health Organisation’s (WHO) essential medicines. However, after the malaria parasites, Plasmodium falciparum and Plasmodium vivax began exhibiting resistance to the drug in the 1960s and 1980s, respectively, it was replaced by similar antimalarial compounds and combination therapies.

Chloroquine is still widely used against the three other species of plasmodium and to treat autoimmune disorders and some cases of amebiasis, an intestinal infection caused by the amoeba Entamoeba histolytica.

Chloroquine’s antiviral properties were explored in the mid-1990s against HIV and in the following decade against severe acute respiratory syndrome, or SARS, which is closely related to the novel coronavirus. In 2004, researchers in Belgium found that chloroquine inhibited replication of SARS in cell culture. The following year, however, another team at Utah State University, United States, and the Chinese University of Hong Kong evaluated a gamut of compounds against SARS replication in mice infected with the virus, finding that chloroquine was only effective as an anti-inflammatory agent. They recommended that it could be used in combination with compounds that prevent replication. Nevertheless, in 2009, the Belgian group found that lethal infections of human coronavirus OC43, a relative of SARS, could be averted in newborn mice by administering chloroquine through the mother’s milk.

According to the study published in Cell Research journal, chloroquine raises the pH in host-cell lysosomes, which interferes with viruses’ attempts to acidify the lysosomes, a prerequisite to the formation of the autophagosomes that cells use to eat themselves. The researchers found that the drug was effective at inhibiting the virus as it was both entering and exiting cells.

Indeed, chloroquine, an old antimalarial is being repurposed for the clinical trial treatment of COVID-19. The drug was first tested in vitro (in the lab) using standard assays to measure the effects on the cytotoxicity, virus yield and infection rates of COVID-19. The drug was reported to function as antiviral at both the entry and post-entry stages of COVID-19 infection. Chloroquine has also recently been reported as a potential broad-spectrum antiviral drug.

In a very recent publication, chloroquine was reported in a press briefing by the State Council of China, indicating that chloroquine phosphate had demonstrated marked efficacy and acceptable safety in treating COVID-19 associated pneumonia in a multi-center clinical trials conducted in China. The study involved 10 hospitals in Wuhan, Jingzhou, Guangzhou, Beijing, Shanghai, Chongqing and Ningbo, and 100 patients. The investigators reported that chloroquine phosphate is superior to the control in inhibiting pneumonia associated with COVID-19, and shortening the course of the disease.

Little wonder the National Agency for Food and Drug Administration and Control (NAFDAC) ordered the manufacturing of chloroquine for emergency stock for possible clinical trial treatment of COVID-19.

Also, President Donald Trump of the United States had penultimate week through the United States Centre for Disease Control (CDC) deployed hydroxyl chloroquine and other drugs for the emergency treatment of patients with the deadly virus in the United States and reports showed that the drug is performing tremendously well in clinical trials.

Director-General of NAFDAC, Prof. Christianah Mojisola Adeyeye, told journalists that other researchers in France, US have used the drug for clinical trial treatment of COVID-19 and they reported effectiveness of the drug and that Lagos State will be starting a clinical trial on chloroquine to evaluate the effectiveness.

Meanwhile, Artemisia annua is a medicinal plant whose use has long been reported in China, where it is locally known as qinghao. It is now grown commercially in many African countries. Also known as Sweet wormwood, A. annua yields artemisinin and the derivatives of this compound are potent antimalarial drugs. Artemisinin is an endoperoxide sesquiterpene lactone that is effective against multidrug-resistant malaria and is also known to act on P. falciparum, the Plasmodium species that causes cerebral malaria. The clinical efficacy of this drug and its derivatives is demonstrated by an immediate and rapid reduction of parasitemia following treatment. Since the WHO recommended the use of artemisinin-based combination (ACT) therapies for malaria in 2001, a number of other forms of A. annua have appeared as antimalarial remedies, including tea bags made from the plant’s leaves.

According to the study published in the journal Microorganisms, Artemisia annua (qinghao) is a plant of the Asteraceae family, which has been used for ages in traditional Chinese medicine. The sesquiterpene lactone artemisinin (ART), the active principle, was discovered in the 1970s. Since then, chemical structural modification studies have been performed to obtain new compounds with enhanced antimalarial activity and improved pharmacological properties. ART derivatives are safe and well-tolerated drugs. This safety is one of the reasons why they have been studied for their efficacy in other diseases beyond malaria. ART derivatives are active against other parasites, cancer cells and viruses, although with lower potency, with effective concentration (EC50s) in the micromolar range, compared to the nanomolar range as antimalarials.

The majority of the literature describes the antiviral effect of ART derivatives in vitro toward human cytomegalovirus (HCMV).

Art, the active principle extracted from Artemisia annua, is poorly soluble in water and oil; thus, the development of semisynthetic derivatives was necessary for appropriate formulation. Poor physicochemical properties may account for the scarce literature about the use of ART as an antiviral. ART, dihydroartemisinin (DHA) and artesunate (AS) were compared for their anti-HCMV effect in a fibroblast cell model by measuring viral Deoxy ribo nucleic Acid (DNA)/genetic material synthesis in cellular lysates. ART showed the lowest activity, even when fractional doses and daily repeated administration were used to counteract the problem of instability of the compounds in a culture medium.

Compared to other compounds from traditional Chinese medicine, ART and AS were also the most active, with low toxicity, for the inhibition of the hepatitis B virus (HBV), measured by hepatitis B surface antigen (HBsAg) and DNA release in a culture medium. Moreover, synergism with the antiviral lamivudine was demonstrated. ART downregulated the oncogenic human papillomavirus (HPV) 39 proteins E6 and E7 in an in vitro model of cervical carcinoma. These results partially confirmed the report by Disbrow and colleagues, who observed an antiproliferative effect of DHA on canine oral papillomavirus.
ART also inhibits hepatitis C virus (HCV) replicon replication, and the effect is synergistic with hemin, an iron donor.

Finally, ART showed inhibition of HIV replication, but the effect was not reproducible in different cell models.

According to a study published in Journal of Traditional and Complementary Medicine, extracts from Lycoris radiata, Artemisia annua, Pyrrosia lingua, and Lindera aggregata have also been documented to display anti–SARS-CoV effect from a screening analysis using hundreds of Chinese medicinal herbs.

In fact an editorial in the journal Nature Plants titled “Redeploying plant defences” noted that epidemic diseases are not a new phenomenon, but easy access to transport in the modern world has accelerated their spread. Perhaps some botanical understanding can help slow them down.

According to the report, the complicated secondary metabolism of plants has been the source of countless medicinal compounds and leads for drug discovery. It is little surprise then that plant products and their analogues have been employed as an early line of defence against COVID-19. On 17 February, the Chinese State Council announced that chloroquine phosphate — a structural analogue of quinine, originally extracted from the bark of cinchona trees — could be used for treating COVID-19 patients. This anti-malarial also has broad-spectrum antiviral activity and regulatory effects on the immune system. Clinical evaluation of chloroquine phosphate in more than ten hospitals across several provinces in China has shown that it alleviates the symptoms for most patients and expedites virus seroconversion.

The epidemiologist Nanshan Zhong, who is credited with discovering the SARS coronavirus in 2003 and is advising on the management of the COVID-19 outbreak, has said that chloroquine phosphate is not a highly effective cure but its effects deserve attention, even though its pharmaceutical mechanism remains unclear. However, quinine and quinine derivatives have been used for two hundred years, and the bark from which it is extracted for far longer. Their safe usage and potential side effects are well established.

Another compound from herbal remedies recruited to control COVID-19 is diammonium glycyrrhizinate, an extract of liquorice roots. Liquorice, Glycyrrhiza glabra, has long been employed against coughs and colds as well as to settle disturbed digestion, while diammonium glycyrrhizinate has anti-inflammatory activity and is used to treat liver damage caused by hepatitis B. Professor Hong Ding of Wuhan University has proposed a combination of diammonium glycyrrhizinate and vitamin C as a COVID-19 therapy. This approach became popular through social media and reporting in publications such as the Health Times (Jiankang Shibao). It has not been officially recommended, but clinical trials have recently been approved.

The rich tradition of herbal medicine in China is also being deployed against COVID-19. In the newest version of the diagnosis and treatment plan issued by the National Health of Commission of China, traditional Chinese medicine decoctions are explicitly recommended. Several patent herbal drugs, such as Huoxiang Zhengqi capsules, Lianhua Qingwen capsules and Radix isatidis granula, are being proposed as treatments, the latter two having also been used during the SARS-CoV outbreak in 2003. Boli Zhang, a leading traditional Chinese medicine expert advising on COVID-19 management, claims that such herbal medicines have been very useful in improving symptoms such as coughing, weakness and digestive system disorders as well as alleviating anxiety.

Compared to chemical drugs, herbal medicines and plant natural products are less understood mechanistically, but several clinical investigations have been started to more precisely evaluate their effects. For example, a project led by Nanshan Zhong aims to investigate the effects of Lianhua Qingwen on COVID-19. As Zhong says, drug development in Chinese medicine is largely based on experiences from clinical practices, which is philosophically different from the routine drug development strategy, and so may have several advantages.

In routine drug development, researchers first discover a drug molecule with potential therapeutic activity against a certain target, then optimize its structure and validate its function using in vitro experiments followed by animal and clinical trials. By contrast, many herbal drugs have been used in clinics for hundreds or thousands of years, and thus their safety and effects have been repeatedly tested; chloroquine phosphate has been used to treat malaria for over 70 years. Timeliness is another advantage, particularly during emergencies. Once an herbal decoction or component is found to be effective, it can be immediately used for treating patients, its safety already established.

Anti-viral herbal medicines have been used in many historic epidemics, for example the previous two coronavirus outbreaks (SARS-CoV in 2013 and MERS-CoV in 2012), seasonal epidemics caused by influenza viruses and dengue virus. Extracts from Lycoris radiate, Artemisia annua and Lindera aggregate, and the natural products isolated from Isatis indigotica, Torreya nucifera and Houttuynia cordata, showed anti-SARS effects. The plant flavone baicalein can prevent dengue virus entry into the host and inhibit post-entry replication6. Additionally, natural products from Pelargonium sidoides roots and dandelion have anti-influenza activities, as they inhibit virus entry and key viral enzyme activities.

Like chloroquine phosphate, these herbal medicines are generally not highly potent and thus cannot be regarded as a cure. Nevertheless, as a complementary treatment, they can elevate recovery rates when combined with other treatments. In an emergency like the current COVID-19 outbreak, drugs like remdesivir — an experimental drug developed against Ebola and recently held up by WHO Assistant Director-general Bruce Aylward as the only “drug right now that we think may have real efficacy” — take time to pass clinical trials, but readily available herbal medicines and natural products with proven safety can buy time as a first line of defence.

Plants are important not only for food but also for medicine. Understanding the taxonomy, ecology and conservation of herbs, as well as the pathways of secondary metabolite synthesis, is important for drug development. Investing in research into ethnobotany, phytochemistry, plant physiology and ecology will be vital in protecting the global population from current and future pandemics.

Meanwhile, Azadirachta indica (neem) is a medicinal plant and has been grown for its universal importance in recent years. Neem has been extensively used in Ayurveda, Unani, and Homeopathic medicines. It has a huge range of chemically and structurally different biologically active chemicals. More than 140 chemically active compounds have been isolated from different parts of this plant including that are flowers, leaves, seeds, roots, fruits, and bark and are being used traditionally as a cure for many diseases. These active compounds have been identified as anti-inflammatory, anti-ulcer, anti-hyperglycaemic, immune-modulator, anti-mutagenic, anti-carcinogenic, anti-oxidant, and anti-viral drugs.

Neem elements are mainly divided into two groups: Non-isoprenoids and Isoprenoids. The non-isoprenoids comprise of proteins, sulphurous compounds, carbohydrates and polyphenolics including dihydrochalcone, flavonoids, coumarin, and aliphatic compounds. The isoprenoids consist of di-terpenoids and tri-terpenoids, which include azadirone, protomeliacins, limonoids and some derivatives such as nimbin, vilasinin, salanin and azadirachtin. By an alcoholic extract of neem leaves a dose-dependent substantial decrease in blood pressure has also been reported.

A study published in the journal BMC Complementary Medicines and Therapies concluded: “Due to strain variations among influenza virus, it is the need of the time to identify the conserved residues among different strains as a target for universal drug discovery based on compounds extracted from natural sources like the neem leaves. In the present study, nucleoprotein was selected and screened against compounds extracted from neem leaves using in-silico screening and molecular docking simulation techniques. The compound Hyperoside from neem leaf extract along with drugs LGH, Naproxen, BMS-885838 and BMS-883559 showed best interactions with conserved residues of the nucleoprotein. So these compounds have been identified for holding great potential for utilization as a universal drug against influenza strains. These observations require further considerations for in-vivo and in-vitro validations.”

The study is titled “Designing and screening of universal drug from neem (Azadirachta indica) and standard drug chemicals against influenza virus nucleoprotein.”