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More antiviral plants to treat COVID-19 validated

By Chukwuma Muanya
07 October 2021   |   12:45 am
Scientists have validated more plants with antiviral activity for the treatment of COVID-19 and other diseases including malaria.

Scientists have validated more plants with antiviral activity for the treatment of COVID-19 and other diseases including malaria.

Top on the list are Azadirachta indica (neem), Psidium guajava (guava), Allium sativa (garlic), wheat germ agglutinin, Mangifera indica (mango), Garcinia kola (bitter kola), Artemisia annua, Moringa Oleifera, Vernonia amygdalina (bitter leaf), Nauclea pobeguinii, Argemone mexicana, Citrus aurantiifolia (lime), Andrographis paniculata (green chiretta), Combretum micranthum, Nauclea latifolia (African pincushion tree) and Morinda lucida (brimstone tree).

The study published in the journal Frontiers Pharmacology is titled “Therapeutic Potentials of Antiviral Plants Used in Traditional African Medicine With COVID-19 in Focus: A Nigerian Perspective.”

The researchers are from: Department of Pharmacognosy and Drug Development, Faculty of Pharmaceutical Sciences, University of Ilorin, Ilorin, Kwara; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ibadan, Ibadan, Oyo State; Department of Pharmaceutical Chemistry, Obafemi Awolowo University, Ile-Ife, Osun State; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, Jülich, Germany; Department of Medical Microbiology and Parasitology, College of Medicine, University of Ibadan, Ibadan, Oyo State; Nestle Nigeria Plc, Ilupeju Avenue, Lagos; Department of Pharmacognosy, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Osun State; Centre for Drug Discovery, Development and Production, University of Ibadan, Ibadan, Oyo State; and College of Basic Medical Sciences, Chrisland University, Abeokuta, Ogun State.

Also, following the urgent need for effective antiviral drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, several natural compounds are under study for their antiviral potential.

A new study, published in International Journal of Molecular Sciences, reports the antiviral activity of Wheat Germ Agglutinin (WGA) against SARS-CoV-2 and its two Variants of Concern (VoC) – Alpha and Beta.

Many natural substances have been studied for their antiviral activity against a variety of viruses. Since the coronavirus 2019 (COVID-19) pandemic, the focus has been testing natural substances for their potential antiviral effects against SARS-CoV-2. To that effect, many naturally derived compounds are undergoing clinical studies.

Lectins, a class of naturally derived compounds, are proteins that bind carbohydrate structures. They have the potential to bind viral envelope glycoproteins and exhibit antiviral activity against several viruses.

A lectin from Triticum vulgaris (wheat) is also known as Wheat Germ Agglutinin (WGA). It demonstrates antifungal activity. It has applications in cell imaging and the potential for improved drug delivery.

However, no studies are testing its antiviral activity against SARS-CoV-2.

In this in vitro study, the researchers have investigated the anti-SARS-CoV-2 potential of WGA.

Infection experiments were performed to examine the antiviral activity of WGA against SARS-CoV-2. Vero B4 cells were infected with a Wuhan type SARS-CoV-2 isolated from a patient. These infected cells were then treated with different concentrations of WGA. SARS-CoV-2 replication was reduced due to WGA treatment. Moreover, this reduction was dose-dependent. This was the first evidence that showed that WGA demonstrates antiviral activity.

Since lectins, in general, are viral entry inhibitors, a similar mode of inhibition was expected with WGA. To test this, the researchers pre-incubated the SARS-CoV-2 patient isolates with different concentrations of WGA and then infected Vero B4 cells. WGA completely blocked the viral infection of cells. Therefore, it acts as an entry inhibitor. WGA may physically interact with the virus and neutralize it. Direct binding of WGA to SARS-CoV-2 viral particles was confirmed through pull-down assays.

Previously, WGA has been shown to exert cytotoxic activity on different cancer cell lines, such as pancreatic, liver, bone, and skin cancer cells. It exhibited time- and dose-dependent cytotoxicity towards acute myeloid leukemia cells in low doses, while no effect on normal cells was observed. Though WGA demonstrates antiviral activity, it will have no therapeutic potential if it is toxic to host cells. Therefore, the researchers performed toxicity assays in all cell lines used for the study. WGA showed no cytotoxic effect. The toxic dose varied among the tested cell lines, but there was still a broad therapeutic window of several log stages.

The antiviral activity of WGA was also tested against two SARS-CoV-2 variants – Alpha and Beta. Cell infection assays were done with Calu-3 cells. WGA inhibited infection of cells by the Alpha and Beta variants, but at different concentrations.

WGA inhibitory activity against other viruses
The researchers also tested the antiviral activity of WGA against human coronavirus (hCoV) OC43, another member of the Betacoronavirus family. And also Rhinovirus serotype 1A (hRV1a), human Rhinovirus serotype 8 (hRV8), and Coxsackievirus A10. WGA exhibited moderate antiviral activity against endemic hCoV OC43. Conversely, WGA did not inhibit binding and replication of other virus families, causing upper respiratory tract infections.

Exploring natural substances rather than synthetic drugs for therapeutic potential is advantageous because natural compounds have better toxicological profiles with larger therapeutic windows, fewer side effects, and a faster admission process. Natural substances have demonstrated their beneficial effects against many diseases, including metabolic disorders or cancer. They have also shown promising results against different viruses, including SARS-CoV and Middle East respiratory syndrome virus (MERS-CoV).

Since WGA reduced infection of SARS-CoV-2, it can be postulated that it could prevent the transition of a mild COVID-19 infection to a severe stage of the disease. This study paves the way for future preclinical research testing the prophylactic and therapeutic potential of WGA. Since its mode of action is exerted via binding the viral particle, WGA could be an ideal candidate for a nasal or throat spray.

This study suggests that WGA could provide beneficial prophylactic and therapeutic effects. Due to its low cytotoxicity, the broad therapeutic window, and the rich availability in nature, it would be an easily distributable agent in the current pandemic and future pandemics.

Meanwhile, according to the study published in Frontiers of Pharmacology, phytomedicines with a long history of use in traditional medicines and bioactive compounds obtained from them have been shown to exert antiviral, anti-inflammatory and immuno-modulatory effects and these bioactivities have been proposed to be linked, following their ability to modulate the immune response and in parallel reduce viral or parasite load. These desirable dual antiviral effects have been demonstrated in indigenous plants used in Traditional African Medicine (TAM) for the treatment of various viral diseases. For instance, Combretum micranthum is one of the main constituents of an indigenous Nigerian antiviral phytomedicine called “Seven Keys to Power” used in the traditional management of smallpox, chicken pox, measles and Human Immuno-deficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS).

In addition, Ritchiea capparoides has been used by herbalists in the eastern part of Nigeria for the treatment of chickenpox, smallpox and hepatitis, while Cajanus cajan is used in ethno-veterinary medicine for the treatment of several viral diseases of cattle in Northern Nigeria. However, rigorous, robust and well-validated scientific investigations are needed to turn these potential antiviral remedies to clinical use. At this time, these data are not available, thus limiting their application.

A typical medicinal plant is a biological factory of a plethora of complex bioactive metabolites and most of the phytomedicines used in TAM are polyherbal with potential multiple targets in host and/or pathogen structure. For instance, the interaction between the spike glycoproteins of SARS COV-2 and the host cell angiotensin converting enzyme 2 (ACE2) receptors which leads to viral attachment and entry, culminating in COVID-19 could be prevented or blocked effectively by anti-adhesive phytocompounds such as phenolics, tannins and polysaccharides reported in some African antiviral plants including Adansonia digitata, Andrographis paniculata, Combretum micranthum, Macaranga barteri, Azadirachta indica.

Plant-derived cysteine knot peptides including antimicrobial peptides and defensins whose bioactivities like other types of defensins are able to block viral infection by clustering the viral particles and blocking receptor binding.

Antimalarial drugs derived from medicinal plants used in Traditional African Medicine have been found useful as repurposed drugs in managing other diseases including viral infections such as HIV, Ebola, and other viral hemorrhagic diseases due to lack of effective therapeutic agents. The active constituents of these plants have various mechanisms of action, which are often not fully elucidated against malaria parasites. The complexity of these constituents sometimes lead to side effects that have been studied for repurposing them for the treatment of other conditions such as non-malaria infectious diseases. The geographical distribution between malaria and viral diseases where malaria endemic regions of the world such as Africa and Asia appear to experience relatively low cases of COVID-19-related mortalities led to the consideration of a possible therapeutic convergence between antimalarial plants (which have continued to be used against malaria in Africa) and viral pathogens including the dreaded SARS CoV-2. One possible explanation attributable to this unresolved therapeutic convergence is the mechanism of activity of these medicinal plants; several antimalarial phytomedicines which tend to produce more bioactivity as antioxidants, anti-inflammatory and immuno-modulatory may function both as antimalarials and antiviral since the underlying mechanism of activity is not directly targeting the pathogen but rather boosting the immunity of the host, effective and efficient resolution of early inflammatory/anti-inflammatory cytokines and scavenging of generated lethal free radicals. This school of thought has been put forward to explain why many widely used African phytomedicines have gained more anecdotal claims of efficacy yet they do not easily kill the malaria parasite in vitro but produce good in vivo activity. For instance, Adebayo et al. (2017) demonstrated the poor in vitro but potent in vivo antimalarial activity of disulphide-rich peptide fraction of Morinda lucida. These antimicrobial peptides have been reported to possess immuno-stimulating and antioxidant activities as well as antiviral property.

A treatise of antimalarial plants used in TAM with documented antioxidant, anti-inflammatory and immuno-modulatory activities as well as level of documented evidence has been presented. However, the authorisation of the repurposed use of these botanical antimalarials should be evidence-informed with impressive clinical data and supported by the best evidence. Considering repurposing antimalarial African traditional phytomedicines for COVID-19 management, endemic and naturalized African plants, which have shown therapeutic promise, as antimalarials following clinical studies should be considered, and these include Vernonia amygdalina, Nuclea pobeguinii, Argemone mexicana, Artemisia annua, Citrus aurantiifolia and Morinda lucida.

Interestingly, available evidence indicates that these promising antimalarial plants additionally have the potential to tackle oxidative stress, regulate inflammatory response and stimulate the immune system to overcome complications observed in COVID-19. Overwhelming evidence supports the standardisation of the leaf and seed of Moringa oleifera for a possible clinical application as it has demonstrated broad range of antiviral activity in various studies while the disulphide-stabilised miniproteins (Morintides), lectins, hevein-like peptides, protein hydrolysates and glucosinolates/isothiocynates isolated from the plant have shown impressive effects, including as anti-adhesives, anti-inflammatory, antioxidants and immuno-modulatory compounds.

Morinda lucida

Traditional African Medicines of the D. R. Congo and Nigeria have developed Nauclea pobeguinii and Nauclea latifolia for clinical application in malaria therapy, which may form a starting point for herbal repurposing for COVID-19 management. For instance, a diherbal preparation containing N. latifolia and Cassia occidentalis (Manalaria®) was authorised for malaria treatment in D.R. Congo, which later formed part of the Congolese List of Essential Drugs. While in Nigeria, aqueous extracts of N. pobeguinii (codenamed PR 259 CT1) was successfully taken through preclinical investigation and phase 1 of clinical trials [Level I, for malaria] for the treatment of uncomplicated malaria and could offer hope in COVID-19 management after requisite investigative screening and standardisation. Furthermore, the aqueous root extract of N. latifolia otherwise known as NIPRD AM1®, has been clinically studied in uncomplicated malaria and found to be therapeutically helpful as an antimalarial and should therefore be given attention for investigative management of COVID-19 [Level I, for malaria].

MAMA Powder and MAMA Decoction are authorised indigenous polyherbal antimalarials, which have been scientifically formulated by Prof. Anthony Elujoba, the Head of the Village Chemist located within Obafemi Awolowo University, Ife, Osun State. MAMA Powder contains stem bark of Alstonia boonei (Apocynaceae) and seed of Picralima nitida (Apocynaceae) while MAMA Decoction is made up of the leaves of Mangifera indica (Anacardiaceae), Alstonia boonei (Apocynaceae), Morinda lucida and Azadirachta indica. In an in vivo experiment using rodents, MAMA Decoction showed antimalarial activity at 240 mg/kg without any observable toxic effect when administered up to 2 g/kg body weight. Human observational study has further reinforced the in vivo activity while the efficacy claims by treated patients on MAMA herbal remedy has multiplied malarial patients’ demand for the herbal medicine. An elaborate preclinical study with superior scientific quality, documentation of chemical fingerprint as well as clinical trial and a possible repurposing for COVID-19 management is encouraged.

Azadirachta indica (Neem) (Dongoyaro, Margosa) Meliaceae, is a medicinal plant with more than 140 chemically active compounds isolated from the different parts including its flowers, leaves, seeds, roots, fruits, and bark and had been employed in managing many diseases. The active compounds have been identified as anti-inflammatory, anti-ulcer, anti-hyperglycaemic, immune-modulator, anti-mutagenic, anti-oxidant, antiviral and anti-carcinogenic drugs. The earliest three active constituents to be characterized namely nimbin; nimbidin and nimbinene were described in 1942. Since then several compounds have been isolated and characterized and were shown to be chemically similar and biogenetically derivable from a tetracyclicterpenes. The neem kernel accumulates liminoids responsible for the bitterness and also found in other plant species such as Rutaceae and Simaroubaceae. Their biological activities include pesticides, anti-feedants and cytotoxic properties. The leaves yielded quercetin and nimbosterol as well as liminoids (nimbin and its derivatives). Quercetin and Beta-sitosterol were the first flavonoid and phytosterol purified from the fresh leaves of neem and were known to have antifungal and antibacterial activities. Although the mechanism of action has not been fully elucidated, it is speculated that the observed therapeutic role of Azadirachta indica is due to the rich source of antioxidant and other valuable active compounds, which include azadirachtin, nimbolinin, nimbin, nimbidin, nimidol, salannin and quercetin.

An earlier study reported the virucidal activity of the leaf extract of A. indica against Coxsackievirus B-4 whose mechanism was proposed to be via interference with an early stage of the virus replication cycle. In a recent study, the in vivo intraperitoneal administration of methanol extracts of A. indica at a dose of 25 mg/kg body weight to murine hepatitis virus infected mice significantly reduced the expression of viral Nucleocapsid protein at the acute stage of infection. Since the murine hepatitis virus represents a prototype coronavirus, the therapeutic potential of the flavonoid, phytosterol and terpenoid-rich extracts of A. indica has been reinforced. In vitro, Neuro-2A cell-line treated with 200 μg/ml methanol extracts of A. indica inhibited virus-induced cell-to-cell fusion. More recently, a computational prediction of SARS-CoV-2 structural protein inhibitors from A. indica indicated their potential to inhibit the functionality of membrane and envelope proteins [Level IV]. The free radical scavenging activity has been linked to the presence of nimbolide and azadirachtin while the anti-inflammatory activity is thought to be via the regulation of pro-inflammatory enzyme activities including cyclooxygenase (COX) and lipoxygenase (LOX) enzyme [Level IV]. This plant, although a component of some polyherbal antimalarial remedies including MAMA Decoction, has not been extensively validated pre-clinically, clinically and standardized as an anti-infective remedy and therefore deserves further scientific attention especially as a potential herbal remedy in COVID-19 treatment.

Therefore, application of Neem in health management includes the use of its leaf, flower and stem bark in disease prevention because of its strong antioxidant potential. The anti-inflammatory activity has been related to suppression of the functions of macrophages and neutrophils relevant to inflammation by nimbidin. Other findings revealed immuno-modulator and anti-inflammatory effect of the stem bark and leave extracts, and antipyretic activities of the seed oil. The antimicrobial activities of Neem include inhibition of growth of organisms such as viruses, bacteria and pathogenic fungi. The antimalarial activity of extracts using Plasmodium berghei revealed reduced level of parasitaemia with the limonoids being the active ingredients. Another study using Plasmodium falciparum also showed significant reduction in both gametocytes and asexual forms of the parasite. Few of these studies lack depth and will require further work to make this plant an interesting candidate for clinical evaluation.

There are several compounds from various African plants that have been proven to have antimalarial properties, which may provide researchers with starting points for antiviral drug discovery. Indoles with antimalarial properties have been derived from two plants species growing in Cameroon such as Penianthus longifolius (Menispermaceae) and Glossocalyx longicuspis (Siparunaceae). The compounds include Palmitine from P. longifolius, Linodenine from G. brevipes. Also from Nigeria plant, there is Fagaronine from Fagara zanthoxyloides (Rutaceae) and Alstonine from Picralima nitida (family Apocynaceae). Triphyophyllum peltatum (Dioncophyllacea) is a tropical African plant from which a potent antimalarial alkaloid, Habropetaline A was isolated. The compound showed good effect against P. falciparum, without cytotoxicity, with respective IC50 values 5.0 and 2.3 ng ml−1 for the strains K1 (Chloroquine and pyrimethamine resistant) and NF54 (sensitive to all known drugs). It was found to be almost as active as artemisinin and one of the most potent natural products used against P. falciparum. There are several observations that point to the fact that naphthoisoquinoline alkaloids are promising lead compounds for the development of anti-malarial drugs which of course could be tried against viral pathogens. Cryptolepines from Sida acuta (Malvaceae), a plant growing in Ivory Coast showed a good antimalarial activity. Cryptolepis sanguinolenta of the family Periplocaceae growing in diverse regions in Africa, have also exhibited potent anti-malarial properties. Following a recently reported in silico experiments, several of these antimalarial alkaloids from African plants have shown interesting predicted inhibition of SARS CoV-2 viral proteins and this support the need for further in vitro, in vivo and clinical investigation on their therapeutic potential for COVID-19 treatment.

Bisnorterpenes, purified from the roots of Salacia madagascariensis of the family Celastraceae, a shrub found in East Africa whose roots are used in the treatment of malaria fever and menorrhagia specifically in Tanzania for its potent antiprotozoal activity. Recent in silico studies supports the anti-SARS CoV-2 activity of bisnorterpenes such as 22-Hydroxyhopan-3-one and 6-Oxoisoiguesterin which have been isolated from endemic African plants with impressive binding affinities for the 3CLpro of coronaviruses of −8.6 and 9.1 kcal mol−1 respectively. Aframomum exscapum (Zingiberaceae) synthesises acyclic triterpenes compounds such as S-nerolidol isolated from the seeds and represents an important constituent of essential oils used in the treatment of malaria. This compound is also found in Artemisia herba and in Cymbopogon citratus/lemon grass (Poaceae), and is able to arrest development of the intraerythrocytic stages of malaria and as such may be considered in future search for anti-viral agents including SARS-CoV-2. Hyptis suaveolens from Nigeria has also yielded abietane-type diterpenoid endoperoxide, a molecule with high anti-plasmodial activity. Sesquiterpenes and sesquiterpene lactones derived from Vernonia spp. are known to have interesting anti-plasmodial activities. Vernodalin is the most active compound in bitter leaf. The plant has many uses in Traditional African Medicine. The leaves of Vernonia amygdalina (bitter leaf) are used in the treatment of various diseases including malaria and viral infections.

Meanwhile, the Nigerian government through the National Agency for Food and Drug Administration and Control (NAFDAC) is now processing not less than 21 herbal formulations for “safe use” under listing status. These polyherbal formulations according to NAFDAC have been claimed to boost immunity with a parallel anti-infective activity capable of providing relief to symptoms associated with COVID-19. More so, a documented evidence of clinical trial, which is required to support efficacy claims, is lacking until the time of this writing. However, the Bioresources Development Group (BDG), Abuja, Nigeria; International Center for Ethnomedicine and Drug Development (InterCEDD) Nsukka, Nigeria, has submitted the previously NAFDAC listed IHP Detox tea for clinical trials which is titled: “Efficacy and safety of IHP Detox Tea (a special blend of Andrographis paniculata (Acanthaceae), Garcinia kola (Clusiaceae) and Psidium guajava (Myrtaceae) for treatment of COVID-19): a pilot placebo-controlled randomized trial”. The clinical trial is to be undertaken at the Nigeria Centre for disease Control (NCDC) COVID-19 isolation site in Lagos, Nigeria and has been registered with the Pan African Clinical Trials Registry: at www.pactr.org with registration number of PACTR202004761408382. The identified main bioactive phytoconstituents of the Andrographis paniculata is andrographolide while kolaviron; Garcinia biflavonoids has been reported in Garcinia kola.

Other indigenous anti-COVID-19 herbal remedies and polyherbal formulations listed by the Nigerian NAFDAC but still lack clinical trial data and not yet authorized for use by the government but available in the market space include: IHP Garcinia, IHP Detox, IHP Immunovit (products of (InterCEDD, Nigeria), CUGZIN capsule, 290 mg (produced by PaxHerbal, Nigeria) and VIVE active (Rx Agroprocessing, Nigeria). The Nigerian Federal Ministry of Health in collaboration with NAFDAC is supporting three foremost and promising remedies for funding considerations to enable clinical trials in a bid to champion an evidence-informed use of indigenous phytomedicines in Nigeria.

For instance, evidence-based and documented scientific publications on the antiviral and immuno-modulatory potentials of African plants could provide some clues on prevention and management of COVID-19. Examples of such African plants widely used in traditional medicine across the region, which have received in silico anti-COVID19 screening for bioactivity include Mangifera indica, Manihot esculenta (Euphorbiaceae), Anacardium occidentale, Uraria picta (Fabaceae) and Corchorus olitorius (Malvaceae). Others are simply immune boosters including V. amygdalina, M. oleifera and Telfairia occidentalis (Cucurbitaceae) among others. Findings from this preliminary study have limited evidence until in depth preclinical and clinical studies are done. Some commonly used Nigerian medicinal plants that may have potentials for the symptomatic management of COVID-19 include: Capsicum (Solanaceae), Zingiber officinale, Xylopia ethiopica (Annonaceae), Carica papaya, Allium cepa, Garcinia kola, Allium sativum. Several other antiviral plants used in Nigerian ethnomedicine such as Senna siamea (Fabaceae) and Zephyranthes candida (Amaryllidaceae) could also be of scientific interest for further research. Tannins and glucosinolates with broad anti-infective activities from seeds of Moringa oleifera, a popular and widely used tropical plant may equally be of research interest as potential prophylactic and anti-COVID-19 herbal supplement. Bridelia ferruginea is another tropical plant for future investigation against COVID-19; it is popular in African ethnomedicine to fight difficult infectious diseases as well as a prophylactic in some anti-infective remedies. Psidium guajava has shown interesting broad-spectrum antimicrobial activities, good antiviral property and polyphenolic compounds (catechin-133, quercetin-73 and gallic acid – 54) derived from the stem bark and leaves have been linked with the reported bioactivity. Howbeit, this study lacks in vivo and clinical evidence as only preliminary in silico and a more elaborate in vitro data has been documented.

A recent CADD-directed fluorogenic enzyme inhibition assay reported corilagin and rhoifolin, two natural products of African origin, with micromolar range inhibitory activity against the main protease (3CLpro) enzyme of the SARS-CoV2. Interestingly, the investigation which had commenced with the screening of an over 1.2 million virtual compound library identified corilagin and rhoifolin in the top eight compounds with respect to main protease inhibitory activity. Corilagin, an ellagitannin, is widely distributed in several African plants and is known to be present in the plant families including Euphorbiaceae (example Acalypha wilkesiania and Acalypha australis, Euphorbia longana, Phyllanthus emblica, P. urinaria, P. tenellus, P. niruri), Geraniaceae (Geranium sibiricum), Combretaceae (Terminalia catappa), to mention a few. Rhoifolin on the other hand is a tri-substituted flavone and has been reported in Uraria picta, a perennial tropical plant with distribution extending through most parts of Sub-Saharan Africa. With in vitro inhibitory activities of both natural products in the micromolar range, it is yet to be determined if the reported potencies will extend to in vivo situations. But the establishment of the SARS-CoV2 3CLpro inhibitory activities for both natural products further support the potential of African plants to potentially furnish herb-based remedies and lead compounds that can be developed into clinically useful treatment for COVID-19 [Level III].

Artemisia annua is the main active component of the claimed anti-COVID-19 herbal formulation popularly called COVID organics by Madagascar. In another study, 75, 52 and 5 per cent of CYP3A4 were respectively inhibited by100 μg/mL grapefruit oil, Eucalyptol and menthol. Curcumin (40 µM), 6-gingerol (100 µM), citral (250 µM), d-limonene (400 µM), β-caryophyllene (500 µM), 1,8-cineole (1 mM), myrcene (1 mM) shows inhibitory effect on CYP3A4; piperine has been shown to enhance bioavailability. These bioactive plant metabolites, which have demonstrated antiviral properties, have been reported in several plants used in TAM for the symptomatic treatment of COVID-19 in Nigeria.

Garcinia kola (bitter kola) is widely used in TAM, the West African sub-region in particular, for a host of conditions including infectious diseases and management of upper respiratory infections. GARCINIA-IHP, used for symptoms of cold and sore throat, pains, cough, nasal congestion, viral infections and inflammation, is one of the herbal health products marketed by InterceDD Health Products in Nigeria. This herbal formulation is

currently under consideration as a repurposed remedy in COVID-19 management after successful clinical trials. As a result of the radical media promotion of claims on Garcinia kola in COVID-19 prevention and management which lacks scientific evidence, the seed of the plant has become one of the many other local herbal recipes consumed without any control by a majority of people in West Africa. The correct doses of bitter kola to achieve the best therapeutic effects and without any adverse side effects are often not followed. However, scientific report suggests that Garcinia kola induces CYP3A4 transcription by a multiple of 3.7-factors in HepG2 cells at 90 μmol/L increasing the possibility for herb-drug interaction. Future investigations will therefore focus on the extensive in vitro and in vivo anti-SARS CoV-2 activities of extracts of Garcinia kola, in depth toxicity studies and a holistic investigation of a possible herb-drug interaction.

Allium species (Allium cepa and Allium sativum) are widely used in Traditional African medicines for the management of infectious diseases and has since been regularly canvassed by some of the COVID-19 infected users in West Africa for the prevention and symptomatic management of COVID-19. These species are among the recipes recommended by the traditional leadership of the Yoruba ethnic nationality in Nigeria and are claimed to be efficacious in COVID-19 prevention and “cure”. Garlic oil, obtained from A. sativum bulb contains sulphur-compounds such as diallyl sulphide (DAS), diallyl disulphide (DADS), and diallyl trisulphide (DATS) which induce CYP2B and NAD(P)H quinone oxidoreductase 1 (NQO1). DAS facilitate the induction of CYP2B10 mRNA and also activate human CYP2B6 and NQO1 promoters, which are primarily regulated by constitutive androstane receptor (CAR) and nuclear factor E2-related factor 2 (Nrf2) transcription factors, respectively. Further investigation is therefore needed to unveil the mechanisms of possible herb-drug interaction.