Searching nature-based solutions to emerging diseases: a preliminary review of Cameroonian medicinal plants with potentials for the management of COVID-19 pandemic

Fongnzossie Fedoung Evariste, Biwole Achille Bernard, Nyangono Biyegue Christine Fernande, Ngansop Tounkam Marlène, Patrick Akono Ntonga, Essono Damien Marie, Forbi Preasious Funwi, Tonga Calvin, Nguenang Guy Merlin, Kemeuze Victor, Sonwa Denis Jean, Tsabang Nole, Isabelle Sandrine Bouelet, Tize Zra, Boum Alexandre Teplaira, Momo Solefack Marie Caroline Betti Jean Lagarde, Nouga Bissoue Achille, Lehman Leopold Gustave, Mapongmetsem Pierre Marie, Ngono Ngane Annie, Ngogang Yonkeu Jeanne 12

Because this 2019-nCov is spread by human-to-human transmission via droplets or direct contact (Lai et al., 2020), its emergence in China has caused a large global outbreak. According to the European Centre for Disease Prevention and Control, the situation update worldwide shows that since 31 December 2019 and as of 29 october 2020, a total of 44,574,981 cases of COVID-19 have been reported worldwide, including 1, 175, 279 deaths (ECDC, 2020). During the same period, African continent has reported 1,750,331 cases (21,793 cases reported for Cameroon and 426 deaths); the countries reporting most deaths being South Africa (19,111), Egypt (6,234), Morocco (3,506), Algeria (1,941) and Ethiopia (1,451).
Despite the ongoing efforts to manage the disease, no specific vaccine or antiviral drug currently exist for the prevention or treatment (Chen et al., 2020), or many months may be required for their development. However, the spread of the COVID-19 pandemic is very dynamic and growing around the world. In response to this outbreak, the World Health Organization, on January 30, 2020 declared that the pandemic constitutes a public health emergency of international concern and issued temporary recommendations under the International Health Regulations.

Global therapeutic response to COVID-19
Currently, no approved drug for COVID-19 exists and treatments provided worldwide to the affected persons are symptom based. These include antiviral drugs so far used against major groups of viruses like human immunodeficiency virus (HIV), herpes, hepatitis, influenza, SARS-CoV and MERS-CoV, antimalaria drugs, imunostimulants, anti-inflammatory drugs that may be effective against elevated levels of cytokines and useful in inhibiting viral infection (Vellingiri et al., 2020). A review by Vellingiri et al. (2020) and Liu et al. (2020) reported that the current most clinically used drugs include: -Arbidol: a drug targeting S protein/ACE2, it is an inhibitor that may disrupt the binding of viral envelope protein to host cells, thus preventing viral entry to the target cell. It has been used earlier as influenza antiviral drug; -Chloroquine/Hydroxychloroquine: anti-malarial drugs, which has been effective in the treatment of avian influenza A and has also shown to have anti-viral as well as immune modulating properties. It can elevate endosomal pH and consequently interfere with ACE2 glycosylation; -Favipiravir: broad spectrum anti-viral drug, this is a purine nucleoside whose possible mechanism on COVID-19 is through its action as an alternate substrate leading to inaccurate viral RNA synthesis; -Lopinavir: a protease inhibitor that wa used along with another flu drug, oseltamivir and resulted in complete recovery of patients showing signs of COVID-19 related pneumonia; -Nitazoxanide: drug so far used in various helminthic, protozoal, and viral infectioncaused diarrhea that may inhibit viral protein expression; -Remidesivir: an anti-viral peptidewhich was used in treatments against Ebola, SARS-CoV and MERS-CoV; -Ribavirin : a broad-spectrum antiviral drug used in the treatment of hepatitis C, in combination with interferon α (IFN); -Sofosbuvir: a drug also used for the treatment of hepatitis C in combination with interferon or RBV; Worldwide, a number of drugs which have so far been proven to be safe for humans are currently being repurposed to be used for the management of this disease.
The 2019 novel coronavirus genome encodes several structural proteins, including the glycosylated spike (S) protein that functions as a major inducer of host immune responses. This S protein mediates host cell invasion via binding to a receptor protein called angiotensin-converting enzyme 2 (ACE2) located on the surface membrane of host cells. Hence, the interaction between viral S protein and ACE2 on the host cell surface is of significant interest in the therapeutic response process since it initiates the infection process.

Herbal medicine and the COVID-19 challenge: a global overview
Globally, herbal treatments have been proven effective to control contagious disease during the 2003 severe acute respiratory syndrome (SARS) outbreak (Zhang et al., 2020). Therefore, since the outbreak of COVID-19, there has been great attention paid on investigating metabolites secreted by plants that may be developed as medicines for  Historically, traditional medicine and local beliefs have always played a role in situation of epidemics through times (Zhang, 1996). A review by Jassim and Navi (2003) reported numerous potentially useful medicinal plants that need to be evaluated and exploited for therapeutic applications against genetically and functionally diverse viruses' families. Keyaerts et al. (2007) identified a variety of plant lectins as antiviral compounds against the SARS-CoV. Lelesius et al. (2019) also showed that some extracts of plants including Thymus vulgaris and Desmiodium canadense were effective against avian infectious bronchitis virus, a highly contagious respiratory disease in chickens caused by a corona virus that belongs to the Coronaviridae family.
From all over the world, people are witnessing a deep attachment to popular medicine to protect themselves against COVID-19.
Africa is endowed with diverse environmental conditions and a diversity of pathogenic microbes species (bacteria, fungi, and viruses), suggesting that African plants could accumulate chemopreventive substances more than plants from the northern hemisphere (Mahomoodally, 2013). Basically, more than 80% of the population in this continent is known to rely on traditional medicine for their primary health care needs.
In Burkina faso, the country's plan to respond to the COVID-19 pandemic does not rule out the use of herbal medicines and clinical trials are underway on Apivirine, a phytomedicine from Benin which is alleged to be effective against the coronavirus (Sputniknews, 2020).
In Mexico, newspapers have reported the use of amulets to protect individuals from COVID-19 (Le Point International, 2020).
In Algeria, to face the spread of this pandemic, consultation of herbalists in the search of traditional antiviral and anti-flu recipes have significantly increased (Le Point International, 2020). Goothy et al.(2020) supported the possible role of medicinal plants in Ayurveda's medicine for the management of Corona virus disease . Sharma and Kaur (2020) showed that Jensenone from Eucalyptus essential oil was a potential inhibitor of 2019 corona virus.
In China, DU Hong-Zhi, et al. (2020) argued that traditional chineese medicine is an effective treatment for 2019 novel coronavirus pneumonia.
More recently, the Malagasy Institute for Applied Research developed an herbal tea based on Artemisia annua (COVID Organics), claiming preventive and curative properties against COVID-19 (Midi-Madagascar, 2020).
In China, herbal traditional medicine have been proven effective to control contagious disease during the 2003 severe acute respiratory syndrome (SARS) outbreak and a recent screening of Chinese herbal medicine database have confirmed that herbal treatments classically used for treating viral respiratory infection contain chemical compounds that have potential anti-2019-nCoV activity (Zhang et al., 2020).
In Cameroon, since the first case was reported in the country, several herbal recipes have been popularized in social media as alledged solutions to manage COVID 19.
According to a recent release from the Cameroon Radio and Television Corporation, the Archbishop of Douala, His grace Samuel Kleda has made public an attempt at treating symptoms of the COVID-19 with a herbal remedy, free of charge and the Ministry of public health is showing commitment to support the process of development and homologation of this treatment (Crtv, 2020).
As the world is currently seeking treatment for COVID-19, there is an urgent need to boost up research so as to develop effective and affordable therapeutics.

Cameroon's response strategy to COVID-19
In Cameroon, access to health care services is challenging. One out of every 1000 patients are able to see a specialist and 3 out of 20 patients are able to buy prescribed drugs in hospitals (Kuete and Efferth, 2010). In this context, the COVID-19 situation is likely to worsen as the country steped into phase 2 of this pandemic marked by a shift from virus importation to intra-community transmission. Based on this situation, Several treatment protocols including the Chloroquine-based treatment suggested by Professor Didier Raoult (Colson et al., 2020) are being tested with more or less mitigated results.
However, since the outbreak of this disease, ethnobotanical and ethnopharmacological research geared at bringing the potentials of traditional medical knowledge into the debate over the management of this disease has been lacking. Yet Cameroon is a biologically diversed Country. Located in Central Africa, at the heart of the Congo Basin, the second world-largest rainforest after the Amazon, its floristic potential scores more than 7850 plant species recorded at the national herbarium. This ranks Cameroon among the country with high level of biodiversity in Africa. Despite the inaccuracy of statistics, the medicinal plants are important elements of health care services. However, access to such plants has so far been largely through traditional healers and herbal markets which are part of an informal economy. The huge volume of published researches on medicinal plants in Cameroon surprisingly contrasts with the paucity of approved phytodrugs. The increasing use of traditional medicines, the general weakness in translating research into concrete drug discovery and development, the evolution of international regulations on access to genetic resources and the growing concern by stakeholders vis-à-vis the demands for patenting rights, evidence of safety, efficacy, good quality traditional medicinal products and a range of other ethical issues, the shortage of essential infrastructure in both the public The findings of this review study will provide other researchers with opportunities to identify the right medicinal plants to be evaluated from a perspective of developing new drugs to combat COVID-19.
2. Methodological approach 2.1. Theoretical framework to the selection of potential anti-COVID plants The theoretical framework for the study is based on a 3-steps review approach.
First, we acknowledge that the use of medicinal plants for the treatment of viral infections in our traditional societies is ancient. Meanwhile, COVID-19 is a novel disease and consequently not yet known in our traditional knowledge system on diseases. However, evidence from existing literature supports the management of symptoms similar to those of COVID-19 using a diversity of plant-based recipes.
Recent review by Adhikari et al. (2020) presented the most commonly reported symptoms of COVID-19. Those considered in this review were: fever/malaria, runny nose, cough, myalgia or fatigue, body pains and sore throat. This review is based on the assumption that, a plant that has been used to manage at least 3 common symptoms of COVID-19 is a potential source of anti-COVI-19 molecules.
Secondly, the inhibitory effect of some secondary metabolites from medicinal plants on the 2019 novel corona virus protease have been reported by Zhang et al. (2020) in China, Mohammadi and Shaghaghi (2020) in Iran and Khaerunnisa et al. (2020) in Indonesia. In this regard, the identification of Cameroonian medicinal plants with potentials as antiCOVID-19 was based on the investigations on their phytochemical profile to select those that are source materials for these secondary metabolites.
Besides the metabolites cited by the above-mentioned studies, alkaloids are also a rich source of active components of plants that have already been fruitfully developed into various chemotherapeutic compounds comprising Chloroquine, an antimalarial drug reported to be effective for the treatment of COVID-19 and many other viral infections (Moradi et al., 2017 ;Colson et al., 2020;Jianjun et al., 2020). The mechanism of the antiviral activity of alkaloids is based on the inhibition of replication of viruses.
Hence, in this study, a plant known as important source of alkaloid is also considered as potential anti-COVID-19. Similar bioactivity on 2019-nCov was also reported for hydrolysable tannins, natural polyphénols (Khalifa et al., 2020;Adem et al., 2020) and terpenoids (Shagaghi, 2020). Therefore, we also consider of great potential for COVID-19 management plants that are rich sources of these secondary metabolites.
Thirdly, the use of biologics that stimulate the immune responses was suggested by Zumla et al. (2020) as a way to help patients resist the invading virus. There is an abundant literature reporting the use of plants by traditional medicine practitioners to boost the immune system in people living with HIV/AIDS (Upoki Anywar et al., 2020). In addition to the important role of boosting the immune system, evidence from the literature reveal the importance of antimalaria and antiviral drugs in the global therapeutics against COVID-19 (Vellingiri et al., 2020). This is also the case for antiinflammatory drugs that may be effective against elevated levels of cytokines and useful in inhibiting viral infection. Hence, plants with immunostimulant, antiviral, anti-malaria and anti-inflammatory properties are considered in this study as of great potentials for COVID-19 management.

Data collection and computation
This review is based on data available in published literature. Bibliographic

Confirmed anti-COVID19 molecules and their source plants in Cameroon
The main protease (Mpro)/chymotrypsin like protease (3CLpro) from 2019 novel corona virus, is reported to be a potential target for the inhibition of its replication (Lu, 2020 prop-2-en-1-one, and β,β'-(4-Methoxy-1,3 phenylene)bis(2'- -Strong antimicrobial activity -Stimulates the activity of immune cells, -Inhibits the release of TNFαdependent pro-inflammatory cytokines -Inhibits the migration of neutrophilic granulocytes into epithelia, which is a crucial process during inflammation
The families with the greatest number of representatives are Rubiaceae (8 species The greatest number of citations was recorded for three of the six symptoms investigated: fever/malaria, cough and myalgia/fatigue (Table 2). However, leaves, fruits and barks were the most used parts, indicating that their utilization may not severely affect the sustainability of the resource base.

State of knowledge on Cameroonian medicinal plants with confirmed antiinflammatory, anti-viral and immunostimulant properties
Evidence from researches conducted on SARS-COV and COVID-19 shows that the weakening of the immune system is one of the major contributing factors to the increased incidence of COVID complications like pneumonia and mortality in affected patients (Curbelo et al. 2017;Taghizadeh and Akbari, 2020;Prompetchara et al., 2020). These authors argued that improving the immune system response may be effective in reducing the incidence of pneumonia and reduction of inflammation may be effective in reducing the mortality rates due to pneumonia. From the literature data compiled, about 10 species have been documented for their beneficial effect in boosting the immune system. Among these species, 3 were also cited to treat at least 3 symptoms of COVID

Capacity building
One of the main problems facing the use of herbal medicines is the proof requirement of their usefulnes, safety and effectiveness. Unfortunately, research and training activities for traditional medicine practitioners has not received due support and attention. As a result, the quantity, quality, the safety and the efficacy of their herbal preparations are far from sufficient to meet the demands. These weaknesses could be corrected by capacity building and low-cost technologies for the industrial production of traditional medicines to make them more effective, stable, reproducible, controlled, and in galenic forms that can easily be transported. Capacity building will be vital for also organizing the corporation and integrating their practices into the perspectives of modern research and development continuum. By so doing, the indiscriminate sale and advertisement of herbal products in all forms of media without compliance to the existing regulations would be discouraged.

Conservation of medicinal plants and documentation of available knowledge on their use
In face of the current risk of deforestation and degradation, conservation of medicinal plants must be a central focus. In this regard, one of the challenges is the lack of complete and conserved knowledge repository on the national pharmacopoeia and the immense medicinal metabolite diversity among these plants. Such a tool will be vital in providing the scientific community with comprehensive knowledge about metabolite data generation and exploitation in early response strategy to emerging diseases.
Because of the growing environmental degradation and the rapid loss of the natural habitat for some of these plants due to anthropogenic activities, it is becoming increasingly urgent to reinforce medicinal plants conservation and documentation of their uses.
To ensure the sustainability of the resource base, conservation measures for medicinal plants will also be required for continuity of research, development and commercialization of natural medicinal products to address potential risk of overexploitation that may result from excessive commercialization and unsustainable practices. The effectiveness of the future sustainability of local natural ecosystems that harbours these medicinal plants will depend upon conservation management approaches that value the importance of involving local communities. In this light, there are lessons learned from Prunus africana management in the Mount Cameroon area that can fuel the step forward is the establishment of such medicinal plant conservation strategy.
The ratification by Cameroon of the Nagoya protocol on access to genetic resource and benefit sharing opens new and promising avenues to achieve the objectives of conserving the local medicinal plants, ensuring their sustainable utilization and improving their contribution in livelihoods improvement and economic development.
Encouraging private sector involvement in herbal drug development There has so far been only very poor participation of the local private pharmaceutical industries in the field of herbal drug development in Cameroon. There should be incentives developed to attract and stimulated their investment in traditional medicine research, development and commercialization.

Conclusion
The purpose of this stock-taking study was to provide a preliminary review on Cameroonian medicinal plants with potentials to be evaluated and developed as remedy for the management of COVID-19. It appears that the country's medicinal plants potentials is immense and is a promising resource from a perspective of novel drug development against this pandemic. Based on the present findings it can be concluded that medicinal plants can be promising resources for the management of COVID-19 in African herbal medicine in general and Cameroon in particular.
Despite the great potential of local medicinal plants, it is unfortunate that they are still pejoratively refered to as "grand-mother recipes". More than ever, there is a need for