REVIEW COVID-19 (SARS-COV-2) AND MEDICINAL PLANTS – LITERATURE

Covid-19


INTRODUCTION
The new β-coronavirus SARS-CoV-2, which causes the infectious disease COVID-19, The transmission of COVID-19 occurs through contaminated droplets, hands or surfaces, with virus incubation periods between 2-14 days (NETO et al., 2021). Symptoms of the new Coronavirus can range from asymptomatic to the development of severe pneumonia and death, however, the most frequent symptoms are fever, dry cough, muscle fatigue, throat irritation, headache, myalgia, nasal congestion and diarrhea (OLIVEIRA et al., 2020a).
According to data from the World Health Organization (WHO) as of 31 July 2022, over 574 million confirmed cases and over 6.3 million deaths have been reported globally. Given these alarming data, researchers around the world have been looking for new alternatives to control the virus. In the race for an effective treatment, chloroquine and hydroxychloroquine, antimalarials, have become possible options for showing an antiviral effect, however, studies dispute the benefits of chloroquine and hydroxychloroquine, generating uncertainty about the use of these drugs (OLIVEIRA et al., 2020a).
Due to the difficulty of finding an effective therapeutic model, other alternatives are being analyzed in an attempt to help in the treatment of COVID-19. A therapeutic possibility includes ISSN 1982-114X Arquivos de Ciências da Saúde da UNIPAR, Umuarama, v. 26, n. 3, p. 1376-1397, set/dez. 2022 1379 medicinal plants (OLIVEIRA et al., 2020a), as they are part of folk medicine and, in many cases, as the only treatment resource. From the advance in knowledge regarding biological properties and potential use, progress has been made in the incorporation of medicinal plants as complementary measures as a therapeutic form for some pathologies, including antivirals (PESSOLATO et al., 2021).
The study of secondary metabolites of medicinal plants has stood out, in the search for bioactive molecules for the development of phytotherapeutics or phytopharmaceuticals that are effective and safe for the treatment of diseases, including viral infections (JAIN et al., 2020). In this context, molecular modeling using computational chemistry and graphic visualization techniques has been used through the in silico study that seeks substances with inhibitory potential in essential virus proteins such as cysteine-protease 3-chymotrypsin (3CL pro ), an important enzyme for viral replication (QAMAR et al., 2020;SILVA et al., 2020).

MATERIAL AND METHODS
To carry out this study, we opted for a research in the form of integrative literature review.
The integrative review determines current knowledge on a specific topic, as it is conducted in order to identify, analyze and synthesize results of independent studies on the same topic.

Etiological agent
The Coronaviridae family is made up of coronaviruses (CoV) as members. These are singlestranded, enveloped RNA viruses. Until then, there were, in this family, six viruses capable of causing diseases in humans. However, in 2019, SARS-CoV-2 was discovered, a new member of this family that gave rise to "Coronavirus Disease-2019" (COVID-19) (ZHOU et al., 2020). Only four circulate between humans and animals commonly (HKU1, NL63, OC43 and 229E). These viruses were first described in 1966 and are divided into four subfamilies, the alpha, beta, gamma and deltacoronaviruses. The first two groups are responsible for causing coronaviruses in mammals (SINGHAL, 2020;SOHRABI et al., 2020;VELAVAN;MEYER, 2020).
Beta-coronaviruses tend to cause infections in humans with mild or even asymptomatic symptoms. Alpha-coronaviruses are capable of causing severe symptoms in animals and being fatal.
In history, there are already two cases of zoonotic overflow of viruses from this subfamily. The polyprotein encoded in the ORF1a/b area of the non-structural protein can be cleaved by two viral proteases, 3CLpro (papain protease type) and PLpro (chymotrypsin protease type).
Cleavage occurs to generate RNA-dependent RNA polymerase and helicase, which can guide the replication, transcription, and translation of the viral genome. Structural protein S can particularly bind to the host cell receptor. This is the main protein for viruses to enter susceptible cells. Proteins M and E are related in the constitution of the viral envelope, while protein N is associated in the assembly of the virus (BEZERRA et al., 2020;ZHOU et al., 2020).
SARS-CoV-2 has a genetic similarity of 79.6% with SARS-CoV-1 and also has a similarity of 96% with RaTG13, a species of coronavirus found in bats (ZHOU et al., 2020). The main feature of SARS-CoV-2 that differs from other viruses is the receptor binding domain (RBD) of its spike proteins (S) (VELAVAN; MEYER, 2020;ZHOU et al., 2020). This receptor has a strong ability to bind to the angiotensin II-converting enzyme (ACE2), in addition to having similarity to receptors of some pangolin coronaviruses (ZHANG et al., 2020).
Protein S, in the envelope of SARS-CoV-2, consists of two binding domains (S1 and S2). The S1 domain supports the attachment of the virus to the receptor (angiotensin II-converting protein).
The S2 domain collaborates in the mechanism of fusion of the viral membrane with that of the host cell. The angiotensin II converting protein is seen in abundance in the pulmonary alveolar epithelial cells, which allows us to understand respiratory aggravation, transmission, infection pathways and disease manifestations (GOMES et al., 2020).
It is believed that primary viral replication takes place in the mucosal epithelium of the upper respiratory tract (nasal cavity and pharynx), with greater multiplication in the lower respiratory tract (trachea, lungs, bronchi, bronchioles and pulmonary alveoli) and in the gastrointestinal mucosa, which causes a mild viremia. Coronavirus is a pathogen that targets the human respiratory system, triggering SARS-CoV-2, generating acute lung injury, worsening of Acute Respiratory Distress Syndrome (ARDS) or Severe Acute Respiratory Syndrome (SRGA) and the condition of failure pulmonary (GOMES et al., 2020;WHO, 2020;ZHOU et al., 2020).

Epidemiology
SARS-CoV-2 was initially transmitted to humans through bats marketed as delicacies in a central market in the city of Wuhan. Then, after contact, SARS-CoV-2 was shown to have a high potential for dissemination (BEZERRA et al., 2020).
The disease is transmitted through interpersonal contact through droplets containing the virus expelled by the infected individual, through sneezing, coughing or speaking. These droplets are inhaled by people close to the infected person, or remain on surfaces, and can also infect after contact with contaminated objects, when touching the regions of the eyes, nose and mouth (CHAN et al., 2020). In addition, it is assumed that the virus incubation time lasts, on average, five days, but this A study, which investigated the susceptibility of dogs, pigs, chickens, ducks, ferrets and cats to the virus, pointed out that only the last two animals are highly susceptible to the microorganism, with its replication in their respiratory tracts, while in other animals, virus replication was quite low (SHI et al., 2020). On the other hand, another study that tested cats and dogs that had been in contact with owners infected by the virus, did not show positive tests by RT-PCR or presence of antibodies against SARS-CoV-2 (TEMMAM et al., 2020). Although there is no evidence of transmission of the virus from animals to humans, domestic animals must be cared for as family members, in order to use preventive measures to prevent contagion (CDC, 2019b).
Symptomatic people usually present with symptoms of fever, dry cough, tiredness, and, in more severe cases, difficulty breathing. The most severe cases have been more prevalent in the elderly and patients with comorbidities such as cardiovascular disease, diabetes mellitus, chronic respiratory diseases and cancer (GRASSELLI et al., 2020;MCGOOGAN, 2020). Other less common symptoms are nasal congestion, sore throat, headache, conjunctivitis, loss of smell or taste, diarrhea, skin irritation or discoloration of fingers (CORONAVÍRUS BRASIL, 2021).
In adults, the symptoms presented by patients tested COVID-19 positive are fever, respiratory problems, dry cough, sputum, headache, myalgia, fatigue and hemoptysis (YUKI et al., 2020). You can also see gastrointestinal problems such as anorexia, diarrhea, vomiting and abdominal pain.
Secondary conditions and underlying diseases need to be considered in adults, such as arterial hypertension, liver diseases, diabetes, chronic obstructive diseases and vascular diseases. In elderly patients, the manifestation of the condition is similar to other age groups, but with greater damage and existence. Respiratory crisis is the main complaint of such patients, analogous to pneumonia and bronchopneumonia (CAO et al., 2020;XU et al., 2020).

Treatment
According to the National Health Surveillance Agency (ANVISA), a drug is a pharmaceutical product that has the presence of the drug in its formula, usually associated with pharmacotechnical adjuvants, prepared with prophylactic, palliative, curative or diagnostic purposes. However, the practice linked to the consumption of medicines, without prescription or medical advice, is called self-medication (RUBERT; DEUSCHLE; DEUSCHLE, 2020).
However, it is known that the simultaneous administration of a polypharmacy by the same There is currently no specific cure or treatment for SARS-CoV-2. WHO (2021b) has coordinated efforts to seek information about the virus that causes COVID-19 with several ongoing studies in different countries, in order to prevent and treat the disease.
The pharmacological treatment of SARS-CoV-2 infection is supportive, that is, it reduces the symptoms that may appear, such as antipyretics for fever, patient hydration and anti-inflammatory drugs to combat the systemic immune attack (HASÖKSÜZ, 2020). In mild cases, care should be taken on an outpatient basis, with home isolation being essential with guidance from contacts. In addition, it is necessary to carry out hand hygiene, frequently, with soap and water, as well as the bedroom and clothes. The patient must be confined to a closed-door and well-ventilated room, quarantined. These people need to be accompanied by the primary care team for 48-48 hours via telephone or teleconsultation (RAJENDRAN et al., 2020).
In severe cases, if the individual has an oxygen saturation <95%, tachypnea, decompensation of comorbidities, they should be hospitalized in isolation two meters away from other suspected cases (BARBOSA et al., 2020). Intubation for the use of a mechanical respirator is a primordial process when the individual presents hypoxemia, respiratory effort, encephalopathy, respiratory obstructions, among other aspects. Respiratory physiotherapy is essential in the ICU, in the maintenance of ventilatory parameters in mechanical ventilators, in early mobilization to prevent the formation of pressure lesions, adhesions and deformities that reduce range of motion. Certain bronchial hygiene maneuvers, hyperinflation and aspiration are also the function of the physical therapist (LONG et al., 2020;RAJENDRAN et al., 2020).

Vaccines
Vaccine development programs are continuously updated by the World Health Organization (WHO), with projects coming from public and private sources. In March 2021, the Brazilian government sought to adopt the Covax Facility, ten months later, when international negotiations were in the final stages, from that the international and Brazilian press described this episode as a late   DÖRNER, 2020). In the intracellular environment, these drugs block the mobilization of lysosomes in phagocytic cells, which reduces the inflammatory effects (BARBOSA et al., 2020). There are published studies of patients who used hydroxychloroquine in addition to azithromycin and had a drastic reduction in viral load (GAUTRET et al., 2020). In contrast, there are studies that refute the benefit of HQ and CQ, and report that these substances did not influence the effective recovery of patients (SAVARINO et al., 2003;DEVAUX et al., 2020) Remdesevir is an antiviral drug that has been shown to be favorable in the treatment of critically ill hospitalized patients. Its activity occurs in the inhibition of the RNA polymerase enzyme, In this sense, new approaches have been studied since the beginning of the pandemic, using hypotheses from the potential immunomodulatory effects of certain substances, antioxidants, chelating agents, use of vitamins, from herbal and homeopathic medicines or stem cells. Thus, medicinal plants have been gaining ground in the treatment of various pathologies, including COVID-19.

What are medicinal plants
The WHO defines medicinal plant as being "any and every plant that has, in one or more organs, substances that can be used for therapeutic purposes or that are precursors of semi-synthetic drugs" (VEIGA JUNIOR et al., 2005).

Medicinal plants used to assist in the treatment of COVID-19
The Indian neem (Azadirachta indica A. Juss), also known as Margosa, is a plant of Asian origin, specifically native in India. Its phytochemicals are found in various plant organs such as seeds, Nigella sativa, also commonly called "Black Cumin", is a plant native to the Mediterranean Basin, therefore, it is found in nature in countries like the Middle East, Spain or India. Active components such as thymoquinones, present in Nigella sativa seeds, may be one of the molecules capable of blocking the recognition region of HSPA5 or BIP, an immunoglobulin binding protein, responsible for the entry of some viruses such as Ebola and Zica, possibly being useful in reducing the risk of COVID-19, according to the studies analyzed (OLIVEIRA, 2020b).
Alllium sativum, also called common Garlic, is a plant from the East and Southern Europe.
Garlic contains antiviral, antibacterial and immune system stimulant properties, being used as a therapeutic medium in traditional medicine for the treatment of parasitic and viral infections, such as the influenza virus. Through 17 substances found in garlic essential oil -allyl disulfide, allyl trisulfide, Eucalyptus globulus, also named Eucalyptus, is a naturally occurring plant from Tasmania and southern Australia. The eucalyptus oil, extracted from the leaves by the process of steam distillation, performs a great action on the respiratory system, with anti-inflammatory and antiseptic properties due to the presence of eucalyptol, which has a regulatory effect on the nuclear factor kappa B (NK-kB) and protein kinases. It also has stimulant properties and strengthens the immune system, so it is especially recommended against respiratory diseases such as asthma, bronchitis, tuberculosis and sinusitis. Thus, the presence of flavonoid compounds quercetin and hyperoside may be associated with an anti-inflammatory response, desirable in Covid-19 cases (OLIVEIRA et al., 2020a;SOUZA MRN et al., 2020).
Piper nigrum (Black Pepper), also called Round Pepper, native from India, is part of a group of plants used to treat viral infections. In silico tests with the active element piperine, present in the fruit, showed a relevant binding affinity for the SARS-CoV-2 glycoproteins, presenting the property of blocking viral replication (OLIVEIRA, 2020b).
The flower Lycoris radiata, known as the red spider lily, one of the species most used in traditional Chinese medicine, contains as active principle licorine, an alkaloid that has shown the ability to prevent viral replication. In recent decades, licorine has attracted interest because of its analgesic, anti-inflammatory and antiviral properties. This species also has a high selectivity index related to the ability of the compound to contain biological activity without generating toxic effects.
The antiviral action mechanism of this constituent is not clearly described in the researches, however, based on the acquired results, it is valid to consider it as a SARS-CoV-2 inhibitor, since studies already report its expressive biological action as an anti-SARS -CoV (OLIVEIRA, 2020b).
The plant species Scutellaria baicalensis, popularly named scutelaria and skullcap de baical, native to China, has as its main active compound Baicaleína (5, 6, 7-trihydroxyflavone) a flavonoid found in the root of the plant, considered one of the capable natural metabolites of blocking SARS-CoV-2 3CLₚᵣₒ protease in in vitro tests with COVID-19-contaminated cells (OLIVEIRA, 2020b).
Another study reports that the ethanol extract of S. baicalensis and baicalein inhibit the pro-SARS-CoV-2 3CL activity in vitro with IC 50 of 8.52 µg / ml and 0.39 µM, respectively. Both block SARS-CoV-2 replication in Vero cells with EC 50 of 0.74 µg/ml and 2.9 µM, respectively. Although baicalein is mostly active in the post-viral entry stage, ethanol extract also prevents viral entry (LIU et al., 2021).

CONCLUSION
The pandemic generated as a result of the rapid and potential dissemination of SARS-CoV-2 has led the world to a situation of extreme concern, especially on the part of Public Health Institutions.
However, there was a great technological leap in the search for early identification mechanisms, more adequate management and the best therapeutic strategy to be adopted.
Considering the global scenario, where there is no scientifically proven assertive treatment, the use of folk medicine through medicinal plants is a promising opportunity, with the potential to reduce viral replication and modulate the inflammatory response. Furthermore, some biocompounds produced by medicinal plants found in this work were superior to other synthetic drugs currently adopted for the treatment of COVID-19. Therefore, it is considered that the study of medicinal plants is important and should be invested as an alternative tool for the treatment of diseases such as COVID- India (Oliveira, 2020) Lycoris radiata (red spider lily)

Flower
Alkaloid with the ability to prevent viral replication.

Liquorine
Cells contaminated with COVID-19 The antiviral action mechanism is not clearly described, however, based on the acquired results, it is valid to consider it as a SARS-CoV-2 inhibitor, since studies already report its expressive biological action as an anti-SARS-CoV.