key: cord-0999622-sjyrr2bn
authors: Vellingiri, Balachandar; Jayaramayya, Kaavya; Iyer, Mahalaxmi; Narayanasamy, Arul; Govindasamy, Vivekanandhan; Giridharan, Bupesh; Ganesan, Singaravelu; Venugopal, Anila; Venkatesan, Dhivya; Ganesan, Harsha; Rajagopalan, Kamarajan; Rahman, Pattanathu K.S.M.; Cho, Ssang-Goo; Kumar, Nachimuthu Senthil; Subramaniam, Mohana Devi
title: COVID-19: A promising cure for the global panic
date: 2020-04-04
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2020.138277
sha: 4c222bd3e1c78c48931f4e69164fc6ee7bffb5ff
doc_id: 999622
cord_uid: sjyrr2bn

Abstract The novel Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, which is the causative agent of a potentially fatal disease that is of great global public health concern. The outbreak of COVID-19 is wreaking havoc worldwide due to inadequate risk assessment regarding the urgency of the situation. The COVID-19 pandemic has entered a dangerous new phase. When compared with SARS and MERS, COVID-19 has spread more rapidly, due to increased globalization and adaptation of the virus in every environment. Slowing the spread of the COVID-19 cases will significantly reduce the strain on the healthcare system of the country by limiting the number of people who are severely sick by COVID-19 and need hospital care. Hence, the recent outburst of COVID-19 highlights an urgent need for therapeutics targeting SARS-CoV-2. Here, we have discussed the structure of virus; varying symptoms among COVID-19, SARS, MERS and common flu; the probable mechanism behind the infection and its immune response. Further, the current treatment options, drugs available, ongoing trials and recent diagnostics for COVID-19 have been discussed. We suggest traditional Indian medicinal plants as possible novel therapeutic approaches, exclusively targeting SARS-CoV-2 and its pathways.

Most of the species under this head are enzootic and only a few of these species infect humans (Schoeman and Fielding, 2019) . Currently, seven human CoVs (HCoVs) have been confirmed. Specifically, they are named as Human coronavirus NL63 (HCoV-NL63) and Human coronavirus 229E (HCoV-229E), which belong to the alpha-coronavirus genus; whereas Human coronavirus OC43 (HCoV-OC43), Human coronavirus (HCoV-HKU1), SARS-CoV, SARS-CoV-2 and Middle East respiratory syndrome coronavirus (MERS-CoV), belong to the beta-coronavirus genus. HCoV-229E, HCoV-NL63, HCoV-HKU1 and HCoV-OC43 strains of coronavirus cause mild respiratory diseases in humans. The SARS-CoV-2 is a zoonotic virus that belongs to the Coronaviridae family that can infect human and several animal species . The SARS-CoV-2 belongs to the subgenus Sarbecovirus and mostly resembles a bat coronavirus, with which it shares 96.2% sequence homology (Chan et al., 2020a) . Currently, it is thought that SARS-CoV-2 has been introduced to human by an unidentified intermediary animal and then it has spread from human-to-human.

Human coronaviruses are predominantly concomitant with upper respiratory tract illnesses ranging from mild to moderate including common cold. Most of the people may be infected with one or more of these viruses at some point in their lifetime (Killerby et al., 2018) . The SARS-CoV and MERS-CoV are the two major causes of severe pneumonia in human (Song et al., 2019) . A comparative analysis of the symptoms among COVID-19, SARS, MERS and common flu has been explained (Table.1 ). The world observed the sudden emergence of COVID-19 in 2019. The exact origin of the virus, continues to remain as a mystery, to researchers worldwide.

Investigations need to be carried out to pinpoint the exact source of infection. The WHO, on February 11, 2020, officially named the viral disease COVID-19 Guarner, 2020) . The Coronavirus Study Group of the International J o u r n a l P r e -p r o o f Committee on Taxonomy of Viruses named the new pathogen as SARS-CoV-2 (Gorbalenya, 2020) . The predecessor SARS-CoV first emerged in 2002. During its course of infection from 2002 to 2003, 774 deaths were recorded out of the 8000+ infections spread across 37 countries (Peiris et al., 2004) . This was closely followed by the emergence of MERS-CoV at Saudi Arabia in 2012, which caused 858 deaths among the 2494 known infected cases (Zaki et al., 2012) . Similar to its antecedents, the SARS-CoV-2 appeared in December 2019 from the animal kingdom and spread to human populations. The COVID-19 is known to show symptoms slowly over an incubation period of around 2 weeks. During this time the virus replicates in the upper and lower respiratory tract, forming lesions (Chan et al., 2020b) . The general symptoms observed in the infected individuals are fever, cough, dyspnoea and lesion in the lungs . In the advanced stage, the symptoms of this virus show pneumonia which progresses to severe pneumonia and acute respiratory distress syndrome (ARDS) which results in to the need for life-support to sustain the patient's life (Heymann and Shindo, 2020) .

The SARS-CoV-2 belongs to the largest family of the RNA viruses and its genome ranges from 27 to 32 kilobases in size (~125 nanometers or 0.125 microns). It is a single stranded enveloped RNA virus which possess a positive-sense RNA genome also known as (+ssRNA) with a 5'-cap structure and 3'-poly-A tail (Chen, J o u r n a l P r e -p r o o f most important ones are N and S, where the former one helps the virus to develop the capsid and the entire viral structure appropriately and the later one helps in the attachment of virus to the host cells (Siu et al., 2008; Walls et al., 2020) . The S protein has three major sections which are, the large ectodomain, a single-pass transmembrane anchor and a short intracellular tail. These play a major role in anchoring the host cells. Among these sections the ectodomain has two subunits which are, the S1 receptor-binding subunit and S2 the membrane fusion subunit.

These subunits are in the clove-trimeric or crown structure which is the reason coronavirus (corona = crown) got its name (Zumla et al., 2016) .

It has been reported that the SARS-CoV and SARS-CoV-2 have similar kind of receptors, especially the receptor binding domain (RBD) and the receptor binding motif (RBM) in the viral genome (Yin and Wunderink, 2018; Zhang et al., 2020; Tai et al., 2020) . During the SARS infection, the RBM of the S protein gets directly attached to the Angiotension-Converting Enzyme 2 (ACE2) in the human or the host cells (Phan, 2020) . The ACE2 protein is expressed in various organs of the human body mainly in the lungs, kidney and intestine, the prime targets of the coronavirus . The ACE1 and ACE2 have gained recognition as significant regulators of the physiology and pathology of the reproductive system (Pan et al., 2013) . Although, due to the novel nature of the virus, no study has proven that it will reduce men's fertility or sexual potency but medics in Wuhan have suggested the likelihood that the disease can affect the production of sperm leading to low sperm count and the formation of male sex hormones (low libido). In addition, SARS-CoV-2 infects host cell through ACE2 receptors leading to COVID-19 related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system .

Interestingly, it has also been proposed that SARS-CoV-2 mechanism of action in infection of humans is similar to the SARS. It has been reported that the RBM of the SARS-CoV-2 has a major amino acid residue (Gln493) that favours the attachment and fusion of the viral S protein with virus into the ACE2 protein of the human cell especially the one present in the lungs which results in respiratory infections in humans Yin and Wunderink, 2018) . An illustration about the structure and binding of S protein to ACE2 has been depicted (Fig.1) . The simplest and most direct approach to combat SARS-CoV-2 would be to neutralize the virus from entering cells as this has been utilized in previous viruses of its kind (Walker and Burton, 2018) . The key advantage here is the host ACE2 protein does not change, so there is no fear about advantageous mutations that may hinder drug development (Karakus et al., 2020) . These findings suggest that an in-depth knowledge about the receptors and its targets and basis of viral replication would be a stepping stone to find a remedy for the SARS-CoV-2 infection.

After the SARS-CoV-2 virus has entered the human host cells, the next step for its survival is its RNA replication. The viral RNA replication is the most unusual and critical step carried out by the virus for its survival inside the host body. The tools that are required for the process of replication are open reading frames (ORFs), two replicase genes (rep1a and rep1ab), a slippery sequence (5'-UUUAAAC-3') and two polyproteins (pp1a and pp1ab). Both these polyproteins contain the most important proteins of the virus that are the Nsp proteins (Nsp1-11and Nsp1-16), these proteins are a common occurrence in these virus types (Baranov et al., 2005) . Recently, it has been found that, the Nsp 15 protein not only has a vital role in replication but also attacks the immune system of the host during viral replication (Youngchang et al., J o u r n a l P r e -p r o o f 2020). Further these Nsp proteins (Nsp1/2, Nsp2/3 and Nsp3/4) assemble to form the replicase-transcriptase complex (RTC) which creates an environment inside the host body suitable for RNA synthesis and replication. Also, these Nsps have various roles in RNA replication of the virus. Nsp12 codes for the RNA-dependent RNA polymerase (RdRP) domain, Nsp13 is encrypted with RNA helicase domain and RNA 5'-triphosphase, Nsp14 encodes exoribonuclease (ExoN) which helps in replication conformity and finally Nsp16 encodes 2'-Omethyltransferase activity. These evidences prove that Nsp protein has a vital role in keeping the virus alive inside the host body by promoting basic synthesis, replication and translation.

The process of replication in the SARS-CoV-2 similar to SARS-CoV virus is multifaceted and needs more understanding (Fehr and Perlman, 2015; Zhang et al., 2020) . For replication, the genomic RNA contains a 5' end region that has the untranslated leader (L) sequence with the transcription regulation sequence (TRS) present at the descending region of the genome (Brian and Baric, 2005) . The replicase gene encoded enzymes uses the negative RNA genome as a template to develop a few sets of small, overlapping messenger RNA (mRNA) molecules that further gets translated into the structural proteins viz, (N, M, E and S protein) also known as the building block for the production of new viral particles inside the host body, while the positive stranded RNA genome is used as a template to produce the negative strand.

During the replication process inside the human host, the N protein of the virus binds to the genome while the M protein is associated with the membranes of the endoplasmic reticulum (ER). Further with the help of Nsp proteins the RNA gets assembled into a helical twisted structure and buds into the ER lumen. Viral progenies are transferred to the cell membranes by the Golgi bodies and exocytosed into the extracellular space of the human host cell environment. These mechanisms were J o u r n a l P r e -p r o o f discovered in the preceding viruses and may have a pivotal role in SARS-CoV-2 as well (Brian and Baric, 2005; de Haan and Rottier, 2005) . From the replication process of the SARS-CoV-2 it is evident that targeting Nsp proteins could enable us to develop a strategy to overcome this viral infection. Other than replication, other pathways associated with the virus can also be targeted for drug development.

SARS-CoV-2 shares homology with the SARS-CoV but the rate of transmission and infectivity of the SARS-CoV-2 has been remarkable; this accelerated spreading rate may be due to a gain of function mutation, making this novel virus different from the SARS-CoV virus. These changes found in SARS-CoV-2 include, an absent 8a, longer 8b and shorter 3b segments and different Nsp 2 and 3 proteins . Nsp 2 of SARS-CoV-2 consists of mutation that is probably associated with the ability of the virus to be more contagious (Angeletti et al., 2020) . In addition, the orf8 and orf10 proteins are also different in SARS-CoV-2. It may be beneficial to understand the biological function of these proteins. Further, it has been found that more pathogenic viruses contain a furin like cleavage site in the S protein, which is not present in SARS-CoV but present in the SARS-CoV-2 (Coutard et al., 2020) . This may be the reason for increased virulence of SARS-CoV-2. Moreover, SARS-CoV-2 binds the same receptor as SARS-CoV, namely, ACE2 with much higher strength; this could be the reason for the increased transmission rate and its capacity to affect other species with such ease. The S protein has S1 on its N terminal and S2 at its C terminal, and the RBD is present at the S1 region. The S2 domain of the S protein consists of the fusion protein, a second proteolytic site (S2′), followed by an internal fusion peptide (FP) and two heptad-repeat domains preceding the transmembrane domain (TM) and J o u r n a l P r e -p r o o f internal FP is identical between SARS-CoV-2 and SARS-CoV (Coutard et al., 2020) .

From previous studies it was suggested that SARS-CoV-2 might have a similar mechanism as like SARS-CoV to enter the host cell.

The SARS-CoV-2 like other beta-coronaviruses undergoes a few steps to enter into and affect the host cell. SARS-CoV-2 binds to same ACE2 receptor present in the respiratory epithelium and alveoli of the lungs . In SARS-CoV, upon binding to the receptor, proteases are recruited to cleave the S protein into S1 and S2

domains. This cleavage induces a conformational change that activates S2, this is followed by the insertion of the FP into the membrane and membrane fusion occurs facilitating the entry of the virus into the cell. Since the nucleotides are conserved in RBD binding motif that is associated with ACE2, it is possible that SARS-CoV-2 utilizes the same mechanism as well. Once the virus enters the cell, ACE2 gets cleaved and shed by ADAM17 into the extra membrane space. Reduced ACE2 has been known to be concomitant with alveoli injury and increases pulmonary vascular permeability (Li and Clercq, 2020) . This could be due to the conversion of angiotensin I to angiotensin II by ACE2, which is a negative regulator of the reninangiotensin pathway. Angiotensin II stimulated ATIR results in the lung pathology associated with respiratory distress (Li and Clercq, 2020) . Once the virus translates its proteins in the cell, the ORF3a protein is produced and codes for a Ca 2+ ion channel that is similar to SARS-CoV and SARS-CoV-2. It interacts with TRAF3 and activates the transcription of the NF-kB pathway, resulting in the transcription of the pro-IL-1B J o u r n a l P r e -p r o o f protein also activates the inflammasome pathway through NLRP3, and this protein is longer in SARS-CoV-2 . The extra nucleotides present in this virus need to be further studied to figure out if that has caused an added advantage. The E protein forming an ion channel, is also conserved in the two viruses and is involved in the overproduction of cytokines through the NLRP3 inflammasome pathway (Nieto-Torres et al., 2015) . All these pathways combined together cause a cytokine storm resulting in respiratory distress a common symptom of COVID-19. Another pathway involved in SARS-CoV includes the JNK pathway; which is activated by ORF3a, ORF3b and ORF7a which may lead to an increased production of pro-inflammatory factors, escalating lung damage (Liu et al., 2014) . The JNK pathway can also be considered as a target for SARS-CoV-2 as it also involves the proteins that are analogous in both viruses.

During the infection of the virus, the most important part is the interaction with the host cell nucleases. It is possible that SARS-CoV-2 may use proteases similar to SARS-CoV such as TMPRSS11a, Trypsin, Plasmin, Cathepsin L and Furin in the cleavage of the spike protein for the virus to enter the cell. These proteases can be used as targets to reduce the symptoms of COVID-19 as proteasomal inhibitors used for HIV treatment are being used in treatment of . A target for the COVID-19 may be advantageous to understand the involvement of the immune system in COVID-19, to explore the possibility of developing specific vaccines for it, as elucidated for previous viruses (Simmons et al., 2013) .

The HCoVs generally are very long (30,000 bp) positive-sense single-stranded RNA viruses. Two groups of protein characterize HCoVs; the structural proteins, and non-structural proteins such as RNA dependent RNA polymerase (RdRp) (nsp12) J o u r n a l P r e -p r o o f (Elfiky, 2020) which could be used as a treatment for the infection. Ultimately, there will be a need for clinical trials to delineate any specific side effects of ACE2-Fc treatment (Kruse, 2020) . Therefore ACE2-Fc might play an important role in the treatment of SARS-CoV-2, if the function of ACE2-Fc is inhibited (Kruse, 2020) . These immunological studies show how crucial it is to understand the basics of the immune responses in these viruses, so these immune cells can be induced to further attack the virus with increased specificity. Besides the immune system, scientists have also found a possible involvement of the COVID-19 in the nervous system.

The COVID-19 are not always confined to the respiratory tract, but they also invade the Central Nervous System (CNS) to induce neurological diseases.

Coronaviruses with such potential are the beta-coronaviruses, including SARS-CoV (Glass et al., 2004) , MERS-CoV (Li et al., 2016) , HCoV-229E (Talbot et al., 1994) , HCoV-OC43 (Dubé et al., 2018) , mouse hepatitis virus (MHV) (Zhou et al., 2017) , and Porcine Hemagglutinating Encephalomyelitis Virus (PHEV) (Mengeling et al., 1972) . According to previous study, coronaviruses may initially invade peripheral nerves and enter the CNS via the synaptic route, where this trans-synaptic transfer has been documented in HEV67 and avian bronchitis virus (Matsuda, et al., 2004) . The first coronavirus found to invade the porcine brain was HEV 67N, and it shares >91% homology with HCoV-OC43 (Li et al., 2016) . Therefore, the neuroinvasive propensity has been demonstrated as a common feature of coronaviruses. Since there is a high similarity between SARS-CoV and SARS-CoV-2, it is quite likely that SARS-CoV-2 may also possess an analogous potential. Based on an epidemiological J o u r n a l P r e -p r o o f survey, the first symptom is dyspnea which occurs in 5 days, followed by hospital admission at 7 days, and intensive care at 8 days for COVID-19 . This latency period is enough for the virus to enter and destroy the medullary neurons.

A possible mechanism about the entry of SARS-CoV-2 inside the CNS has been illustrated ( Fig.3) . Similarly, Mathew (2020) stated that the symptoms might attribute to respiratory disease is due to the inability of air to get into the lungs, that might actually be the defects in respiration controlled by the nervous system. It has been reported that some COVID-19 patients showed neurologic signs, including headache (about 8%), nausea and vomiting (1%). As the neuroinvasion of SARS-CoV-2 is accompanied by respiratory failure in COVID-19 patients, the entry of the virus into the CNS must be prevented. As an emerging virus, awareness of the possible entry of SARS-CoV-2 into the CNS is significant for prevention and treatment. It is also important to find effective antiviral drugs that can cross the blood-brain barrier . Therefore, more innovative approaches are required to detect this viral infection at an earlier period.

During the SARS and MERS outbreaks effective diagnostic tools were developed for accurate detection. Although, useful at that time, it is now essential to develop specific tests for COVID-19. The viral nucleic acid detection is primarily used in SARS-CoV-2 diagnosis . CDC has recommended the collection of upper respiratory nasopharyngeal (NP) swabs for the diagnostic tests (CDC, 2020) . The CDC detection assay targets the N region and consists of one test for beta-coronaviruses and two unique probes for SARS-CoV-2. The Charité algorithm comprises of probes for E protein and RA-dependent RNA polymerase (RdRp). Once both are positive, the sample is again tested against specific SARS-J o u r n a l P r e -p r o o f CoV-2 RdRp (Loeffelholz and Tang, 2020) . Contrastingly, the E protein with RdRp was also detecting SARS-CoV, and so, these assays can be used to test for the SARS-CoV-2 when there are no traces of SARS-CoV (Cordes and Heim, 2020) . When the commercially available Real Star kit, Virus +Rox Vial kit and Super Script III Onestep RT-PCR System with Platinum TaqDNA Polymerase were compared for their efficiency, the RealStar Kit did not have any unwanted signals and exceeded the other two in its performance (Konrad et al., 2020) . These methods can also be compromised due to inadequate sample volume, inaccuracies in methods of testing, not collecting samples at the appropriate time window, and contamination. Similar issues have been identified as potential problems that may diminish the precision of the tests (Lippi et al., 2020) . Moreover, these tests are also expensive, hence cheaper alternatives have been developed to track the symptoms of COVID-19 using smart-phone surveillance (Dorigatti et al., 2020) . Imaging techniques can also be utilized as a diagnostic method in COVID-19. Additionally, chest CT scans have been facilitated to detect lung abnormalities in this SARS-CoV-2 infection .

Abnormalities in the CT scans can be concomitant with disease progression and prognosis. But, not all the cases can be perfectly detected with CT scans (Lei et al., 2020) . Therefore, it is essential to conduct molecular tests and consider travel history and clinical symptoms of the patient as well. As there are an upsurge of infected people, more efficient, quicker and cheaper diagnostic tools must be developed to effectively identify infected individuals. Hence, the integrated approach of imaging and molecular diagnosis would help in screening and treating COVID -19 effectively.

In order to design these specific drugs, it is important to understand the current strategies used to treat this novel COVID-19

Though the number of affected individuals is constantly on the rise, there are no FDA approved drugs for COVID-19 yet. At present, treatment provided to the affected individuals are mainly symptom based, and the seriously ill individuals are provided with organ support (Jin et al., 2020; Zumla et al., 2020) . It is necessary to invest time and effort in identifying vaccines and drugs for this novel virus. Since the development of drugs specific for COVID -19 will take at least a few months drugs which have been proven to be safe for humans can be repurposed to treat this disease.

The vast majority of the drugs used for treatment worldwide falls under any of the following classification of drugs. 

19. Anti-inflammatory drugs especially JAK-STAT inhibitors, used against rheumatoid arthritis, may be effective against elevated levels of cytokines and useful in inhibiting viral infection. According to recent study, an inflammatory drug, baricitinib when used in combination with anti-viral drugs like Remidesivir, increases the potential of the drug to reduce viral infection .

The virus is known to enter the host cells by binding the S protein to ACE2 receptors. By developing neutralizing antibodies against the receptors, there is a high possibility for reducing the severity of the disease (Zheng and Song, 2020) . Currently, only a handful of drugs have been approved for use against SARS-CoV-2.

Even before the declaration of COVID-19 as a pandemic by WHO, there was an immense lack of disease specific drugs. Being a rapidly spreading virus, it is essential to provide timely treatment for the affected individuals (Zumla et al., 2016) .

A list of potential drugs is provided in Table 2 and a few of the commonly used drugs are discussed below;

10.1. Ribavirin -Ribavirin is also a broad-spectrum drug whose therapeutic potential was uncovered during 1972. This antiviral drug is used in the treatment of hepatitis C.

It is usually used in combination with interferon α (IFN). This drug, approved by the 

nucleotide analog, which was used in treatments against Ebola, SARS-CoV and MERS-CoV. It is a promising and potential drug which causes premature termination by entering the nascent viral RNA (Warren et al., 2016) . Currently, it is undergoing clinical trials for Ebola treatment (Mulangu et al., 2019) . Another recent study has shown that Remidesivir scored 0.77 µM at half maximal concentration against COVID-19 and blocked viral infection .

Chloroquine -This drug, classified as an anti-malarial drug, has shown potential in the treatment of avian influenza A (Yan et al., 2013) . Chloroquine also has shown to have anti-viral as well as immune modulating properties. This drug also showed 1.13 µM at half maximal concentration against SARS-CoV-2 and blocked viral infection by increasing the endosomal pH required for viral fusion Vincent et al., 2005) .

J o u r n a l P r e -p r o o f 10.6. Favipiravir -This drug is also a broad spectrum anti-viral drug which has obtained approval from Shenzan Health Commission for treating COVID-19 patients .

Currently, there are numerous companies that have applied for clinical trials to repurpose existing drugs as well as to develop vaccines and drugs to fight against the fast spreading COVID-19 (Rudra, et al., 2017) . In the case of repurposing the existing drugs, randomized controlled treatment (RCT) are being carried out by various biotechnological companies as well as research organizations such as National Institutes of Health (NIH), USA to identify disease specific drugs. The major drugs undergoing clinical trials that have the potential to treat this viral infection (Table 3) .

More research may be required in traditional medicine to utilize them in the treatment of COVID-19.

Indian traditional medicinal systems are considered as one of the oldest treatments in human history and it plays an important role in encountering global health care needs (Ravishankar and Shukla, 2007) . Traditional Indian medicinal practices include Ayurveda, Siddha, Unani and Yoga, Naturopathy and Homoeopathy, which are successfully practiced for treating various diseases (Gomathi et al., 2020) . These practices came into existence 5000 years ago, and these systems have been witnessed and scripted in ancient literature.

Traditional Indian medicine use plants, minerals and animal products for curing human diseases. Traditional knowledge regarding the plant sources and their usage are essential to use them accurately and for the right condition (Tabuti et al., 2003) About 25,000 plant based formulations have been used in folk remedies in J o u r n a l P r e -p r o o f Indian medicine (Pundarikakshudu and Kanaki, 2019) . Recently, the total number of Indian medicinal plants was estimated to be around 3000, yet, traditional practitioners use around 8000 different species for their practice (Pundarikakshudu and Kanaki, 2019) . Traditional medicines are generally ignored in research and development of modern drugs since their translational potentials are often underestimated. Although these medicines are ambiguous, there are wide contexts for their usage in non-Western medical technology (Yuan et al., 2016) . A single herb may contain many phytochemical constituents that function alone or in combination with other compounds to produce the desired pharmacological effect (Parasuraman et al., 2014) .

Due to their use in traditional medicine, many plant molecules have been studied and subsequently modulated into drugs for various diseases (Li-Weber, 2009; Fabricant and Farnsworth, 2001) . The search for new compounds with antiviral activity has often been unsatisfactory due to viral resistance along with viral latency and recurrent infection in immune-compromised patients (Sumithira et al., 2012) . Among antiviral therapeutic methods, the majority of them are non-specific for viruses (Jiang et al., 2015) , 

Since ancient times, Indian herbs have been used as a treatment and preventive strategy for several diseases, including respiratory viral infections. The benefit of using these herbs in viral respiratory infections is to build immune stimulating and inflammation modulating effects of manage the immune system. Holistic approach of AYUSH systems of medicine gives focus on prevention through lifestyle modification, dietary management, prophylactic interventions for improving the immunity and simple remedies based on presentation of the symptoms (AYUSH, 2020). Indian preventive and prophylactic medicinal plants recommended by AYUSH for COVID-19 (Table 4) . Also, other studies on coronavirus using medicinal plants are rather minimal in India, a study has shown anti-mouse coronaviral activity (a

Evolvulus alsinoides in Tamil Nadu (Vimalanathan et al., 2009 ). Among them Vitex trifolia and Sphaeranthus indicus have been found to reduce inflammatory cytokines using the NF-kB pathway, a pathway that has been implicated in respiratory distress in SARS-CoV (Alam et al., 2002; Srivastava et al., 2015) . Clitoria ternatea has been J o u r n a l P r e -p r o o f identified as a metalloproteinase inhibitor, ADAM17, a metalloproteinase that is involved in ACE shredding can be targeted using this plant, as ACE-2 shredding has been associated with an increased formation of viruses (Maity et al., 2012) . The plants Glycyrrhiza glabra (Nourazarian, 2015) and Allium sativum (Keyaerts et al., 2007) have been known to target the viral replication of SARS-CoV, arising as promising candidates against SARS-CoV-2. Clerodendrum inerme Gaertn , another herb has been found to have the potential to inactivate the viral ribosome, this can be further investigated for its utility as a drug targeting SARS-CoV-2 protein translation (Olivieri et al., 1996) . Similarly, Strobilanthes Cusia (Tsai et al., 2020) Verbascum thapsus reduced infections caused by influenza viruses. The molecular mechanism by which these plants target influenza virus can be studied to understand if they attack any molecules overlapping between SARS-CoV-2 and the Influenza viruses. Hyoscyamus niger was found to be a bronchodilator and also had inhibitory effects on Ca 2+ channel (Gilani et al., 2008) . This could be used to target the orf3a Ca 2+ channels that trigger various downstream pathways upon viral infection. Most importantly, various medicinal plants have shown inhibitory effects against ACE, and these include Coriandrum sativum (Hussain et al., 2018) (Yarnell, 2018; Arora et al., 2011; Coon and Ernst, 2004) . It was noted that Andrographis paniculata suppressed increased NOD-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β molecules which are extensively involved in the pathogenesis of SARS-COV and likely SARS-CoV-2 as well .

Salacia oblonga (He et al., 2011) another plant from Tamil Nadu has also displayed suppressive effects on angiotensin II, AT1 signal, which was related to lung damage.

can be promising drugs for COVID-19. They include, Acacia nilotica (Shanti, 2016) ,

Eugenia jambolana (Otake et al., 1995) , Euphorbia granulate (Shanti, 2016) . Some plants like Ocimum sanctum (Rege and Chowdhary, 2014) , Ocimumkilim and scharicum (Thayil Seema and Thyagarajan, 2016) , Solanum nigrum (Yu, 2004) , Vitex negundo (NAIR, 2012) have been known to target the reverse transcriptase activity of HIV and can be studied for activity against SARS-CoV-2 as well. Further, Sambucus ebulus (Ganjhu et al., 2015) has been known to inhibit the activity of enveloped viruses and can also be used to target this virus. These medicinal plants can be used to ameliorate the symptoms of COVID-19. Though many medicinal plants have been identified, a lot of research has to be carried out for the development of drug specific to SARS-CoV-2. Therefore, it is important to explore the effect of these prescribed traditional medicines on SARS-CoV-2 ( 

COVID-19 has emerged as the most dangerous pandemic threat through-out the globe since its outbreak during December 2019. It has become a big challenge for the researchers and virologist to find a solution for this deadly disease. This is attributed to the fact that COVID-19 is a viral infection that has been known to have the fastest frequency of recombination or replication in its positive strand resulting in the quick formation of new progeny viral cells inside the host cells. It has also been reported that SARS-CoV-2 has a high rate of mutagenesis and changes in structure, which has created a barrier for both investigations of the disease and therapeutic regimens (American society for microbiology, 2020). Recently, few researchers have identified that the SARS-CoV-2 has mainly two types of strains, which are the 'L'

and 'S' strains. Among these strains the L strain is more common and may have evolved from the S strain; additionally, this L strain has a higher rate of replication inside the human host cell, which has resulted in the escalation of the infection in limited time. Hence, it has become a big challenge to analyze the condition and offer therapy at the short time available. Due to the high mutation rate, it has been harder to understand the genomic organization and host interaction of the virus (Habibzadeh and Stoneman, 2020) .

The genomic structure of the virus is not the only factor that presents a great challenge to research, its ability to adapt and survive in different environmental conditions make it nearly impossible to identify its mode of survival. It has been earlier reported that the SARS virus can survive at 4°C with a humidity rate of 20%.

The first outbreak of the SARS-CoV-2 was during the peak of winter, where the environmental temperature was around 2°C to 10°C. But since then the virus has 

Over the past few decades, there was an urge to discover the root cause of coronavirus infections not only in animals but in humans as well. Currently, COVID-19 has emerged as the most intense and petrifying viral infection to be handled by the human race. According to WHO (2020b), major concern among public health Further, analyzing and understanding the role of non-structure and accessory proteins encrypted in this virus will aid us in understanding its mechanism of action. Also, acquiring an in-depth framework of its unique RNA replication process will enable us to find a breakthrough point to understand the host immunological response. Our review suggests the importance of a few Indian medicinal plants that have been used for several decades in the treatment of various respiratory conditions. It highlights the pathways that the plant-based medicines may target to reduce the disease burden.

Thus, proactive investments in researches based on Indian medicinal plant derived vaccines or drugs to treat COVID-19 would emerge as a source of light to overcome this fatal infection.

The cases reported in many parts of China and the outbreaks involve large settle on surfaces in the environment further infecting people who breathe these particles or touch these places and then touch their body parts. Hence, it is important to stay more than 1 meter (3 feet) away from a person who is sick (WHO, 2020c).

Reports suggest that older persons and persons with pre-existing medical conditions (such as high blood pressure, heart disease, lung disease, cancer or diabetes) appear to develop serious illness more often than others, also pregnant women with the infection had did not pass the infection to their unborn babies (Wu and McGoogan, 2020; Chen et al., 2020) . Also it has been reported that some of the Asian populations are more susceptible to acquire this COVID-19 infection when compared to the other races populations (Xu, 2020) . Following are the protective measures given by WHO Among the viral structure the S protein has a major role in binding of the virus to the host receptor cells. S protein has two subunits which are the S1 receptor-binding subunit and S2 the membrane fusion subunit; where the earlier one attached itself to the ACE2 receptor of the human host cell and the S2 subunit internalises and creates the membrane fusion among the viral subunit and the ACE2 receptors. This leads to the release of the viral RNA into the host cell and results into respiratory infection.

Possible mechanism of action of SARS-COV-2 Fig.2 : Depiction of the binding of SARS-COV-2 to its receptor ACE-2. The S1 and S2 subunits are subsequently cleaved followed by the shedding of ACE-2 by ADAM 17. This resulting in an increased amount of Angiotensin II leading to respiratory distress. Upon binding, the virus fuses with the membrane and enters the cell, followed by translation, and replication of the proteins. ORF3a, ORF8b,E proteins and the NF-KB pathway activates the inflammasome pathway through various means, leading to the activation of cytokine. This results in a cytokine storm, further resulting in respiratory distress. Fig.3 : Entry of human Coronavirus in CNS through olfactory bulb upon nasal infection which causes inflammation and demyelination. Further it reaches the whole brain via Blood Brain Barrier and CSF via Blood-CSF barrier in < 7 days. The possible entry of SARS-CoV-2 into the Brain and CNS is important to design effective antiviral drugs. Effective drugs that may cross Blood Brain Barrier and Blood CSF barrier may be taken in to consideration while designing and this could be a promising in treatment strategies.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f (Diao et al., 2020) 36.

Interferon Subtypes of β-1b, α-n1, α-n3, and human leukocyte interferon α SARS (Tan et al., 2004) 37. Acyclovir SARS, MERS, Coronavirus 229E and COVID-19 (Peters et al., 2015) 38. Cathespin L SARS (Simmons et al., 2005) 

Pathogenicity and transmissibility of 2019-nCoV-a quick overview and comparison with other emerging viruses

Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection

Thiopurine analogues inhibit papain-like protease of severe acute respiratory syndrome coronavirus

Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings

Treatment of SARS with human interferons. The Lancet

Charged polysaccharides resistant to lysosomal degradation during kidney filtration and renal passage and their use to treat or prevent infection by coronaviruses

Virtual screening of an FDA approved drugs database on two COVID-19 coronavirus proteins

Andrographis paniculata in the treatment of upper respiratorytract infections: a systematic review of safety and efficacy

Rapid random-access detection of the novel SARScoronavirus-2 (SARS-CoV-2, previously 2019-nCoV) using an open access protocol for the Panther Fusion

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furinlike cleavage site absent in CoV of the same clade

Natural products in drug discovery and development

Three decades of antiviral drugs

Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV

Molecular interactions in the assembly of coronaviruses

Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19)

Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43

The past, present and future of antimalarial medicines

Anti-HCV, nucleotide inhibitors, repurposing against COVID-19

The value of plants used in traditional medicine for drug discovery

Coronaviruses: an overview of their replication and pathogenesis

Antiviral effects of Glycyrrhiza species

Sphaeranthus indicus Linn.: A phytopharmacological review

Herbal plants and plant preparations as remedial approach for viral diseases

The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies

Gastrointestinal, selective airways and urinary bladder relaxant effects of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Ca2+ channels

Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice

Drug Studies on Rett Syndrome: From Bench to Bedside

Severe acute respiratory syndrome-related coronavirus-The species and its viruses, a statement of the Coronavirus Study Group

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

Three Emerging Coronaviruses in Two Decades The Story of SARS, MERS, and Now COVID-19

Medicinal plants: traditions of yesterday and drugs of tomorrow

Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques

The Novel Coronavirus: A Bird's Eye View

Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity

The Ayurvedic medicine Salacia oblonga attenuates diabetic renal fibrosis in rats: suppression of angiotensin II/AT1 signaling

COVID-19: what is next for public health

The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells

Aromatic amino acids in the juxtamembrane domain of severe acute respiratory syndrome coronavirus spike glycoprotein are important for receptor-dependent virus entry and cell-cell fusion

Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus

Prediction of potential commercially inhibitors against SARS-CoV-2 by multi-task deep model

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Identification of Hypotensive Biofunctional Compounds of Coriandrum sativum and Evaluation of Their Angiotensin-Converting Enzyme (ACE) Inhibition Potential

A second, non-canonical RNA-dependent RNA polymerase in SARS Coronavirus

Understanding the T cell immune response in SARS coronavirus infection

A distinct name is needed for the new coronavirus. The Lancet

The JAK2 inhibitor AZD1480 inhibits hepatitis A virus replication in Huh7 cells

A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)

COVID-19 (Novel Coronavirus 2019)-recent trends

Breaking the Convention: Sialoglycan Variants, Coreceptors, and Alternative Receptors for Influenza A Virus Entry

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice

In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine

Plant lectins are potent inhibitors of coronaviruses by interfering with two targets in the viral replication cycle

Mechanism & inhibition kinetics of bioassay-guided fractions of Indian medicinal plants and foods as ACE inhibitors

Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors

Human coronavirus circulation in the United States

Rapid establishment of laboratory diagnostics for the novel coronavirus SARS-CoV-2 in Bavaria

Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China

Comprehensive analysis for diagnosis of novel coronavirus disease (COVID-19) infection

Phase I study of intravenous ribavirin treatment of respiratory syncytial virus pneumonia after marrow transplantation

Overview of current therapeutics and novel candidates against influenza, respiratory syncytial virus and Middle East respiratory syndrome coronavirus infections

Therapeutic options for the 2019 novel coronavirus (2019-nCoV)

The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients

The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets

Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases

Protective effects of casticin from vitex trifolia alleviate eosinophilic airway inflammation and oxidative stress in a murine asthma model

Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease 2019 (COVID-19)

Accessory proteins of SARS-CoV and other coronaviruses

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis paniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin

Laboratory Diagnosis of Emerging Human Coronavirus Infections-The State of the Art

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

RNA-dependent RNA polymerase activity in murine coronavirus-infected cells

Standardized Clitoria ternatea leaf extract as hyaluronidase, elastase and matrix-metalloproteinase-1 inhibitor

Acute respiratory distress revealing antisynthetase syndrome

A tale of two cytokines: IL-17 and IL-22 in asthma and infection

Use of asc and asc-cm to treat ards, sars, and mers

Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon

The vagus nerve is one route of transneural invasion for intranasally inoculated influenza a virus in mice

Lost smell and taste hint COVID-19 can target the Nervous system

Treatment of respiratory viral infection in an immunodeficient infant with ribavirin aerosol

Characteristics of a coronavirus (strain 67N) of pigs

Phytochemical, therapeutic, and ethnopharmacological overview for a traditionally important herb: Boerhaviadiffusa Linn

Potential antiviral agents from marine fungi: an overview

A randomized, controlled trial of Ebola virus disease therapeutics

HIV-1 reverse transcriptase inhibition by Vitex negundo L. leaf extract and quantification of flavonoids in relation to anti-HIV activity

Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome

Effect of Root Extracts of Medicinal Herb Glycyrrhiza glabra on HSP90 Gene Expression and Apoptosis in the HT-29 Colon Cancer Cell Line

A systemic antiviral resistanceinducing protein isolated from Clerodendrum inerme Gaertn. is a polynucleotide: adenosine glycosidase (ribosome-inactivating protein)

Screening of Indonesian plant extracts for anti-human immunodeficiency virus-type 1 (HIV-1) activity

Angiotensin-Converting Enzymes Play a Dominant Role in Fertility

Pharmacological screening of Coriandrum sativum Linn. for hepatoprotective activity

Polyherbal formulation: Concept of ayurveda

Severe acute respiratory syndrome

Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Novel coronavirus: From discovery to clinical diagnostics

Boerhaaviadiffusa L. attenuates angiotensin II-induced hypertrophy in H9c2 cardiac myoblast cells via modulating oxidative stress and down-regulating NF-κβ and transforming growth factor β1

Analysis and Regulation of Traditional Indian Medicines (TIM)

Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study

Indian systems of medicine: a brief profile

Antiviral drugs for viruses other than human immunodeficiency virus

Evaluation of Ocimum sanctum and Tinospora cordifolia as probable HIV protease inhibitors

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet

Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus

Utilization of alternative systems of medicine as health care services in India: evidence on AYUSH care from NSS 2014

Coronavirus envelope protein: current knowledge

Recognizing pitfalls in virtual screening: a critical review

Perspective of Potential Plants for Medicine from Rajasthan, India

SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes

Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

The M, E, and N structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles

Novel Coronavirus (COVID-19) Pneumonia with Hemoptysis as the Initial Symptom: CT and Clinical Features

Detection of Middle East respiratory syndrome coronavirus using reverse transcription loop-mediated isothermal amplification (RT-LAMP)

From SARS to MERS, thrusting coronaviruses into the spotlight

A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes

COVID-19: combining antiviral and anti-inflammatory treatments

Antiviral and antioxidant activities of two medicinal plants

Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

Neurotropism of human coronavirus 229E

Inhibition of SARS coronavirus infection in vitro with clinically approved J o u r n a l P r e -p r o o f antiviral drugs

Methanol and aqueous extracts of Ocimum kilimandscharicum (Karpuratulasi) inhibits HIV-1 reverse transcriptase in vitro

Hepatoprotective and antioxidant effect of Sphaeranthus indicus against acetaminophen-induced hepatotoxicity in rats

Antiviral Action of Tryptanthrin Isolated from Strobilanthes cusia Leaf against Human Coronavirus NL63

Medicinal plants of Tamil Nadu (Southern India) are a rich source of antiviral activities

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Passive immunotherapy of viral infections:'superantibodies' enter the fray

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein Cell

Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS

A review of the 2019 Novel Coronavirus (COVID-19) based on current evidence

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Fast Identification of Possible Drug Treatment of Coronavirus Disease-19 (COVID-19) Through Computational Drug Repurposing Study

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

World Health Organization (WHO), 2020a. Laboratory testing of 2019 novel coronavirus ( 2019-nCoV) in suspected human cases

situation-reports World Health Organization (WHO), 2020c.Middle East respiratory syndrome coronavirus (MERS-CoV) -The Kingdom of Saudi Arabia

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV

Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2

Unveiling the Origin and Transmission of 2019-nCoV

Antimalaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model

Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

Herbs for Viral Respiratory Infections

MERS, SARS and other coronaviruses as causes of pneumonia

Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2. bioRxiv

The Extracts of Solanum nigrum L. for inhibitory effects on HIV-1 and its essential enzymes

The traditional medicine and modern medicine from natural products

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov

Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV

COVID-19 and the cardiovascular system

Hepatitis E virus infects neurons and brains

Coronaviruses-drug discovery and therapeutic options

Reducing mortality from 2019-nCoV: host-directed therapies should be an option

References 1. α-interferon Spectrum of respiratory infections¸ RSV and SARS

Reverse transcriptase inhibitors: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine. SARS (De Clercq, 2007) 5. Nucleotide reverse transcriptase inhibitor: tenofovir disoproxil fumarate

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine and efavirenz

Fusion inhibitor: enfuvirtide. Lamivudine and adefovir dipivoxil

J o u r n a l P r e -p r o o f Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J o u r n a l P r e -p r o o f 9. Umifenovir ARVI, influenza, rhinovirus, adenovirus, parainfluenza, respiratory syncytial virus, coronavirus, including the causative agent of atypical pneumonia Used in the phase III trials of 2019-nCoV virus, SARS, MERS 10. 3-chymotrypsin-like protease SARS, MERS (Chou et al., 2008; Kilianski et al., 2013; Li and De Clercq, 2020) 11. Papain-like protease SARS, MERS and Human Coronavirus NL63. (Chen, 2020; Harcourt et al., 2004; Kilianski et al., 2013) 12. RNA-dependent RNA polymerase SARS, Murine Coronavirus. (Imbert et al., 2006; Lu, 2020; Mahy et al., 1983) 13. Capsid spike glycoprotein (hCoV-EMC) SARS, Human Coronavirus Hoffmann et al., 2020; Howard et al., 2008) 14. (Keyaerts et al., 2009 (Keyaerts et al., , 2004 Vincent et al., 2005) 23. ASC09 ARDS, Respiratory distress syndrome, SARS, MERS (March and Bogatcheva, 2019, 2018) J o u r n a l P r e -p r o o f