key: cord-0953161-r1a1emfw authors: Antonio, A.S.; Wiedemann, L.S.M.; Galante, E.B.F.; Guimarães, A.C.; Matharu, A.S.; Veiga-Junior, V.F. title: Efficacy and sustainability of natural products in COVID-19 treatment development: opportunities and challenges in using agro-industrial waste from Citrus and apple date: 2021-08-16 journal: Heliyon DOI: 10.1016/j.heliyon.2021.e07816 sha: 682ced6f9943e54a8eb6fedb209cbac6c9c11ec0 doc_id: 953161 cord_uid: r1a1emfw Natural products have been used in the treatment of illnesses throughout the history of humankind. Exploitation of bioactive compounds from natural sources can aid in the discovery of new drugs, provide the scaffold of new medicines. In the face of challenging diseases, such as the COVID-19 pandemic, for which there was no effective treatment, nature could offer insights as to novel therapeutic options for control measures. However, the environmental impact and supply chain of bioactive production must be carefully evaluated to ensure the detrimental effects will not outweigh the potential benefits gained. History has already proven that highly bioactive compounds can be rare and not suitable for medicinal exploitation; therefore, the sustainability must be accessed before expensive, time-demanding, and large trials can be initialized. A sustainable option to readily produce a phytotherapy with minimal environmental stress is the use of agro-industry wastes, a by-product produced in high quantities. In this review we evaluate the sustainability issues associated with the production of phytotherapy as a readily available tool for pandemic control. On 11th March 2020, a huge new challenge to humankind was established, the COVID- 19 2 pandemic. First reported in late 2019, COVID-19 is a viral disease caused by a novel virus of 3 Coronaviridae family, [1] namely, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-4 2). [2] Since its discovery and to date (June 2021) a staggering 175 million people have been 5 infected by SARS-CoV-2 and 3.7 million have lost their lives. [1] The rate and impact of 6 infection cannot be underestimated and its abatement is an immediate global societal need 7 today. [3] 8 In record time, the scientific community was able to provide a vaccine for COVID-19 to the 9 population. Nearly one year was required to develop 5 different vaccines that are being 10 applied. To date, nearly 2.2 billion doses have already been administrated, [1] yet, only 0.8% of 11 low-income countries population have received any dose. Low and middle-income countries 12 are struggling with sequential waves of COVID-19 contaminations due to absence of means to 13 obtain and distribute vaccines. Such countries are not able to produce the vaccine and are 14 highly dependent of commercial trade. [4] Even though those countries represents 84% of 15 global population, they also represent only 35% of vaccine orders. [5] Yet, in order to control a 16 pandemic, all global population need to receive treatment in the shorter time possible. 17 The challenge in providing global treatment in not merely financial, but also involves the 18 technological capacities of each country to manufacture vaccines, presence of necessary 19 infrastructure for its storage and distribution, and the supply chain of inputs and medicinal 20 products. [6] The supply chain of COVID-19 vaccines is not capable to provide global 21 immunization on short time. In addition, medical products, such as ventilators and sedative 22 drugs, had their demand increased drastically during pandemic, and their supply chain were 23 strained, causing shortage in many regions. [7-9] 24 In pandemic scenarios guarantee a robust supply chain for industry and medical treatment is 25 essential in the process of diseases control, economy maintenance, and society adaptation to 26 the "new normal". Sustainable technologies are one of the research lines that need to be 27 improved in order to achieve such goals. [10] Green methods not only aid the environmental 28 management, but also can build up local empowerment, reducing the dependency of low and 29 middle income countries to international imports and global dependent supply chains, such as 30 those used to provide the COVID-19 vaccine inputs. [6, 10] While global vaccine distribution is 31 not possible, provide a sustainable supportive treatment is mandatory to preserve life. As long 32 J o u r n a l P r e -p r o o f 2. The COVID-19 case 23 The COVID-19 pandemic has become a seriously health public issue, even though its estimated 24 mortality rate is lower than others coronavirus which were also pandemic in the past (SARS 25 and MERS). [23] One of the issues is the vulnerability of people which has comorbidities such as 26 diabetes, hypertension, and many other cardiovascular diseases,[24] that currently have a high 27 occurrence rate globally. [25] The susceptibility of non-communicable comorbidities patients to 28 get severe forms of COVID-19 is related to the inoculation and replication system of the virus. 29 The mechanism of SARS-CoV-2 infection and replication (Figure 1 ) is via the expression 30 downregulation of the angiotensin converting enzyme type II (ACE2). Because of this 31 interaction SARS-CoV-2 affects the homeostasis of the cardiovascular, diabetic and respiratory 32 J o u r n a l P r e -p r o o f processes. Once the virus interacts with ACE2 through the 3 chymotrypsin-like proteases 1 (3CLpro) present on its surface, the virus enters the host cell, which is promoted by protein 2 cleavage of the transmembrane protease serine type 2 (TMPRSS2). At this point on, SARS CoV-3 2 RNA is released inside the cell and the virus starts to replicate. [20] 4 COVID-19 generates several problems to society not only related to mortality. Psychological 5 diseases had exponentially increased, manpower in several production lines had drastically 6 decreased, global economy was severely affected, supply chains in diverse industrial lines 7 collapsed with the increasing demands. The world is not the same as before November, 2019. 8 There are several ways to treat viral diseases, such as drug repurposing, supportive drug 9 development, and vaccine development. Drug repurposing was the first strategy used against 10 Even though the scientific community has managed to develop a vaccine in a record time, 3 there is still much uncertainty. There is no precise information about how long the vaccine will 4 be effective, part of the global population is afraid to be vaccinated, middle and low-income 5 countries cannot afford massive vaccine programs and are depending on other countries for 6 vaccine production. While a few countries are vaccinating their population rapidly and on 7 schedule, too many others are unable to follow the same immunization rhythm, and still have 8 increasing infection rates, which are creating more resistant variants of the SARS-CoV-2 9 virus. [34] In face of such challenges imposed by COVID-19, every available possibility to aid 10 pandemic restrain must be explored. Sustainable options for supportive treatments can be the 11 hope until the vaccines are fully optimized or equally available worldwide. 12 3. Natural metabolites and the SARS-CoV-2 fungi, [40] higher plants, [19] and metabolically engineered organisms. China is one of the major countries which applies phytotherapy in disease treatment. In this 32 country, which is the epicenter of the SARS-CoV-2 pandemic, medicinal herbs were adopted as 33 J o u r n a l P r e -p r o o f supportive treatment to COVID-19, depending on the clinical stage. In Chinese medicine, 1 COVID-19 was treated as a viral influenza-like disorder. The clinical stages are divided into four: 2 Prevention (healthy or asymptomatic patients); early (mild symptoms, such as fever, sore 3 throat, shortness of breath, intestinal disorders); late (pneumonia, obstructing the lung); and 4 recovery (sequelae of diseases, such as deficiency of the lung). to preserve life, several of these questions are related to cost-benefit and risk-benefit. For 3 instance, in the case of chloroquine and hydroxychloroquine, the cost-benefit was accessible, 4 as it was a drug that is well-consolidated in the market. However, the risk-benefit was not 5 accurately measured. The consequence was a great insecurity in whether those drugs are safe 6 or not. After widespread use by society, research have come forth reporting the cardiovascular 7 dangers of those drugs and their little to no efficacy against COVID-19.[71,72] 8 For a bioproduct to be sustainable in a pandemic scenario, several aspects must be carefully 9 considered (Figure 3) , that includes general and specific features of drug and phytotherapy 10 development. [73] Attendance with such aspects can provide treatments capable of being 11 delivered efficiently worldwide thus restraining the pandemic scenario. These aspects briefly 12 involve supply chain, safety, and optimization for worldwide commercialization. 13 A major concern in pandemic control is that the treatment has to be available as fast as 14 possible to all society. The high financial cost of vaccines is one of the drawbacks in the global 15 control of COVID-19. [4] The supply chain regards not only the final availability of the product, 16 but also the availability of any material necessary to manufacture it. In developing 17 bioproducts, the initial concern in the supply chain is the availability of the bioactive 18 compound or bioactive extract and its raw source. 19 For medicinal purposes, several in vitro, in vivo, pre-clinical, and clinical assays must be 20 performed with the drug of interest. Thus, even before pre-clinical testing, a significant 21 amount of the medicine must be available for test. For instance, in pre-clinical trials of a 22 phytotherapy it is recommended that nearly 50 kg of the raw material be available. [74] Raw 23 material in phytotherapy can be any vegetative or reproductive organ, and even byproducts, 24 such as oleoresins and essential oils. In natural conditions, obtaining that amount of raw 25 material can be extremely challenging. For example, the Copaifera genus oleoresin is a 26 worldwide popular phytotherapy, however, each Copaifera tree can present a very distinct 27 quantity of oleoresin. It is estimated that, depending on the species and geographical region, The major advance of agro-industrial waste as raw material in treatment development is that 7 they are constantly produced. In addition, their management also follows a sustainable 8 perspective as less residues will be discharged in nature. of fresh weight) [94] in apple pomace, this residue can be a reliable source, not only to 1 isolate those compounds, but also to create bioactive extracts. 2 Issues concerning the application of apple pomace in COVID-19 treatment development the 3 extraction, isolation, and purification process. The standard method used to isolate ursolic acid 4 from apple pomace includes a pre-treatment with decoction, Soxhlet extraction with 5 increasing polarity solvents, recrystallization and purification on a chromatographic column 6 ( Figure 5 ). [94] The Soxhlet extraction has a yield of ursolic acid of 3.5% with a purity of nearly 7 60%. [94] Similar results can be achieved with the use of UAE (yield of 2.9% and purity up to 8 97%), which can reduce organic solvent residues in the final product, as the developed method 9 uses only methanol. [113] Another advantage of the non-convection extraction method is 10 related to energy consumption and safety, as Soxhlet requires boiling organic solvents. The 11 major issue in the ursolic acid extraction from this matrix is the presence of carbohydrates, 12 which interferes in the purification process. In any case, pre-treatment of the matrix to remove 13 carbohydrates is a fundamental step in order to obtain a high value-added product and 14 increase process efficiency. Providing high quantities of natural product for quick response in a pandemic scenario requires 27 a consistent supply source. 28 The in silico and in vitro tests also suggests that common occurrence natural metabolites, from 29 flavonoids and terpenoids chemical classes, can be promising active compounds in a 30 supportive treatment of COVID-19. The greater advance of such compounds is that they can be 31 found in several plants, including domesticated species. 32 In this scenario, two natural products have drawn attention: the Citrus peel wastes and apple 1 pomace. These bioproducts are rich source of suggested anti-COVID-19 natural metabolites. As 2 they are agro-industrial waste of massive production worldwide, the supply chain is more 3 robust than the ones of Scutellaria and licorice extracts. The domestication and high 4 production make agro-industrial waste more sustainable than in natura bioactive, particularly 5 for the immediate response required for diseases such as COVID-19. 6 Treatment development for such challenging diseases must be fast. Yet, the only concern 7 cannot be in how fast we can obtain an anti-COVID-19 treatment but also the efficacy and 8 sustainability of the new medicine. All development phases must be carefully accomplished 9 and data must be analyzed thoroughly. Science must, and can, solve the problem, while 10 avoiding creating new ones, such as in the case of Taxol. After ensuring initial risk of supply 11 and efficacy, other questions must be addressed, such as production standardization, 12 bioavailability, side-effects, and phytotherapy-synthetic drugs interaction. Using the best of 13 our knowledge on chemical composition of biomass waste materials to take full advantage of 14 natural resources seems to be the proper and sustainable way to increase development with 15 lessons from Ebola May A ff ect COVID-19 Vaccine Development and The deadly 5 coronaviruses: The 2003 SARS pandemic and the 2020 novel coronavirus epidemic in Vaccine production, distribution, access, and uptake 10 Phytomedicine: history, scope and future prospects Marine natural products A review of the microbial production of 17 bioactive natural products and biologics A critical review on exploiting the 20 pharmaceutical potential of plant endophytic fungi 16 Extraction of chili, black pepper, and ginger with near-critical CO2, propane, and 17 dimethyl ether: Analysis of the extracts by quantitative nuclear magnetic resonance Efficient synthesis of baicalin and its analogs Its Occurrence, Distribution, and Role in Nature, 22 Especially in Relation to Insect Behavior and Pollination Ursolic and Oleanolic Acids as Potential Anticancer Agents Acting in 25 the Gastrointestinal Tract Oleanolic acid and its derivatives: 28 Biological activities and therapeutic potential in chronic diseases Molecular Docking of Natural Compounds from Tulsi (Ocimum sanctum) 31 and neem (Azadirachta indica) against SARS-CoV-2 Protein Targets Silico Evaluation of Prospective Anti-COVID-19 Drug Candidates as Potential SARS-CoV-2 Main Protease Inhibitors Recent 38 developments on the extraction and application of ursolic acid. A review Ursolic acid: An overview on its 41 cytotoxic activities against breast and colorectal cancer cells Ursolic Acid and Its Derivatives as 1 Bioactive Agents Review on the potential action mechanisms of 3 Chinese medicines in treating Coronavirus Disease Antiviral natural products and herbal medicines Prospects of honey in fighting against COVID-9 19: pharmacological insights and therapeutic promises Traditional Chinese herbal medicine-potential therapeutic 12 application for the treatment of COVID-19 Efficacy of Traditional Chinese Medicine on COVID-15 19: Two Case Reports Clinical features and treatment 18 of COVID-19 patients in northeast Chongqing A traditional Chinese medicine formula NRICM101 to target COVID-19 23 through multiple pathways: A bedside-to-bench study The Ethnobotany of Copaíba (Copaifera) Oleoresin in the Amazon Potencial de produção de óleo resina de 4 Copaifera multijuga Hayne nos dois períodos climáticos amazônicos na Reserva de Divers. Biológica e Sociocult Oil resin production potential of 9 Copaifera spp natural populations in the Southwestern Brazilian Amazon Assessing the suitable cultivation areas 12 for Scutellaria baicalensis in China using the Maxent model and multiple linear 13 regression Predicting suitable cultivation regions of 15 medicinal plants with Maxent modeling and fuzzy logics: a case study of Scutellaria 16 baicalensis in China High-yield 19 production of scutellaria radix flavonoids (baicalein, baicalin and wogonin) by liquid-20 culture of Scutellaria baicalensis root-derived cells Separation methods used for Scutellaria baicalensis active 23 components Production of plant-specific flavones 26 baicalein and scutellarein in an engineered E. coli from available phenylalanine and 27 tyrosine Using SSR-HRM to identify closely 29 related species in herbal medicine products: A case study on licorice Investigation on medicinal plant resources of Glycyrrhiza 32 uralensis in China and chemical assessment of its underground part Natural resource based green supply chain 35 management, Supply Chain Manag Medically useful plant terpenoids: Biosynthesis, 38 occurrence, and mechanism of action Natural product drug discovery and development: the United States 41 National Cancer Institute role Discovery and resupply of pharmacologically active plant-derived natural products: A 4 review International Food Policy Research Institute, Licorice Industry in China : Implications for 6 Licorice Producers in Food and Agriculture Organization of the United Nations Flavonoids: An overview A High-Yield Process 12 for Extraction of Hesperidin from Orange (Citrus sinensis L. osbeck) Peels Waste, and Its 13 Transformation to Diosmetin, A Valuable and Bioactive Flavonoid, Waste and Biomass 14 Valorization Quantification of Flavonoids in Brazilian Orange Peels and 17 Industrial Orange Juice Processing Wastes Ursolic acid from apple pomace and traditional plants: A 20 valuable triterpenoid with functional properties Multivalorization of apple pomace towards materials and chemicals. Waste to wealth Integrated processing of plant-derived waste to 26 produce value-added products based on the biorefinery concept Food waste: 29 Challenges and opportunities for enhancing the emerging bio-economy Valorization 32 of Waste Orange Peel to Produce Shear-Thinning Gels Toward Renewable-Based Hydrothermal Process for the Production of High Purity Xylo-oligosaccharides from 37 Beech Wood Hemicellulose Synthesis and Characterization of Bacterial Cellulose from Citrus-Based 41 Sustainable Resources Converting citrus wastes into value-added 1 products: Economic and environmently friendly approaches Modern extraction and 4 purification techniques for obtaining high purity food-grade bioactive compounds and 5 value-added co-products from citrus wastes Valorization of 7 pomelo (Citrus grandis Osbeck) peel: A review of current utilization, phytochemistry, 8 bioactivities, and mechanisms of action Citrus fruits are rich in 11 flavonoids for immunoregulation and potential targeting ACE2 No end in sight for the Brazilian COVID-19 crisis Valorisation 16 of citrus processing waste: A review High biological value compounds 19 extraction from citruswaste with non-conventional methods Green Extraction of Essential Oils, Polyphenols, and Pectins from Orange 23 Microwave-Assisted Pectin Extraction at Pilot Scale Biotransformation effects on 29 anti lipogenic activity of citrus extracts How do biocatalysis and biotransformation 32 affect Citrus dietary flavonoids chemistry and bioactivity? A review Exploitation of apple pomace towards 35 extraction of triterpenic acids, antioxidant potential, cytotoxic effects, and inhibition of 36 clinically important enzymes Ultrasonic assisted extraction of ursolic acid from apple 39 pomace: A novel and facile technique