key: cord-0859024-91rvxar9
authors: Dowarah, Jayanta; Marak, Brilliant N.; Chand Singh Yadav, Umesh; Prakash Singh, Ved
title: Potential drug development and therapeutic approaches for clinical intervention in COVID-19
date: 2021-05-25
journal: Bioorg Chem
DOI: 10.1016/j.bioorg.2021.105016
sha: 2f29421c277ff27fcbaf3fb3f530401a26eaf599
doc_id: 859024
cord_uid: 91rvxar9

While the vaccination is now available to many countries and will slowly dissipate to others, effective therapeutics for COVID-19 is still illusive. The SARS-CoV-2 pandemic has posed an unprecedented challenge to researchers, scientists, and clinicians and affected the wellbeing of millions of people worldwide. Since the beginning of the pandemic, a multitude of existing anti-viral, antibiotic, antimalarial, and anticancer drugs have been tested, and some have shown potency in the treatment and management of COVID-19, albeit others failed to leave any positive impact and a few also became controversial as they showed mixed clinical outcomes. In the present article, we have brought together some of the candidate therapeutic drugs being repurposed or used in the clinical trials and discussed their safety and efficacy for the treatment of COVID-19.

enters the cell, it is uncoated and genomic RNA of the virus is then released into the cytoplasm and translated into two polyproteins, namely, PP1A and PP1AB [29, 30] . The viral genome is then converted into a negative-sense viral RNA genome, used as a template to synthesize positive-sense genomic and sub-genomic viral RNA. Genomic RNA and nucleocapsid (N) protein are replicated or transcribed in the host cytoplasm. However, other viral structural proteins, such as spike (S), envelope (E), and membrane (M), are transcribed and translated into the endoplasmic reticulum, which is then inserted into the Golgi body [31] [32] [33] . The viral genomic RNA with N protein and other structural proteins such as S, E, and M are further assembled in the ER-Golgi intermediate compartment (ERGIC) . Finally, the newly generated positive-sense RNA genomes are released through the plasma membrane [33] .

It has been shown that entry of SARS-CoV-2 is not possible in cells without ACE2 expression.

The other coronavirus receptors, such as dipeptidyl peptidase 4 (DPP4) and aminopeptidase N, also do not mediate the entry of SARS-CoV-2, indicating that ACE2 is essential for SARS-CoV-2 entry into the host cell [2] . The studies have shown that the S protein of SARS-CoV-2 has a much higher binding affinity towards ACE2, which is 10-20 fold greater than that of SARS-CoV [34] , making SARS-CoV-2 more contagious than other coronaviruses. ACE2 is highly expressed on type II alveolar epithelial cells making lungs susceptible to SARS-CoV-2 infection [35, 36] . However, its expression on the surface of epithelial cells in the nasopharynx, nasal mucosa, and oral cavity is low. Also, ACE2 is highly expressed on myocardial cells, urothelial cells, and the kidney's proximal tubule cells [35, 36] . Besides, ACE2 and TMPRSS2 are abundantly expressed in the small intestine, particularly in the ileum [37, 38] . ACE2 is also highly expressed in lower airways among smokers and people with chronic obstructive pulmonary disease (COPD), which increases the severity of covid-19 among these people [39] .

It has also been reported that ACE2 level is upregulated by interferons (IFNs) that increase the binding of SARS-CoV-2 via ACE2 [40] . Recent findings showed that overexpression of TMPRSS2 in Vero-E6 cells of African green monkeys considerably elevates SARS-CoV-2 infectivity [41] . Small-molecule serine protease inhibitors such as nafamostat and camostat prevent SARS-CoV-2 entry into host cells in a dose-dependent manner [42, 43] . 

Remdesivir ( Fig. 2) is an adenosine triphosphate derivative having an anti-viral property.

Gilead Sciences initially developed it in 2009 to treat hepatitis C. However, it does not yield positive results against hepatitis C [44] . Therefore it was investigated to treat Ebola virus disease and Marburg virus infections in 2016 [45] . In 2017, Sheahan et al. showed its potential inhibitory activity in human respiratory epithelial cell cultures against SARS-CoV and MERS-CoV with EC50 values of 0.07 µM and 0.069 µM, respectively [46] .

Remdesivir is a prodrug of GS-441524, both of which undergo phosphorylation into an active nucleoside triphosphate in the host cell. The triphosphate form of Remdesivir or GS-441524 is structurally similar to adenosine triphosphate (ATP). Thus it competes with ATP to bind with viral RdRp enzymes. The binding of remdesivir with the RNA strand restricts RNA synthesis, resulting in decreased viral RNA production [47, 48] . , sensitive to SARS-CoV-2 [43] . Remdesivir also has superior antiviral activity than drugs lopinavir and ritonavir, and it effectively inhibited MERS-CoV replication in vitro, with an EC 50 of 0.09 µM. In the nonhuman primate and mice models of MERS-CoV infection, both prophylactic and therapeutic remdesivir enhanced pulmonary function, minimized viral load in lung tissues, and reduced lung lesions' harshness [49, 50] . A case study on the first COVID-19 patient in the USA by Holshue et al. indicated that intravenous administration of remdesivir helped significantly in the recovery of the patient [51] . These findings support ongoing investigations of remdesivir as a potential therapeutic drug for the treatment of COVID-19.

Lopinavir/ritonavir (Fig. 2) , also known as Kaletra, are protease inhibitors approved by the FDA to treat HIV/AIDS infection. This drug is produced by combining a low dose of ritonavir with lopinavir [52, 53] . Lopinavir alone has low bioavailability. However, ritonavir, a potent hepatic CYP-450 3A4 inhibitor, increased the inhibitory activity of protease inhibitors [54] . 

Umifenovir ( Fig. 2) is an anti-viral drug normally used for the treatment of influenza [66] . [71] . The study disclosed that favipiravir is not as effective as umifenovir in the treatment of COVID-19 patients.

Favipiravir (Fig. 2) 

Triazavirin (Fig. 2) is a synthetic purine nucleoside analog and a broad-spectrum antiviral drug initially developed in Russia. It is known to inhibit viral RNA synthesis [79] . It has a broadspectrum antiviral activity in vitro and in vivo against RNA viruses such as influenza A and B

virus, Forest-Spring encephalitis, and tick-borne encephalitis [79] [80] [81] [82] . A phase 2 & 3 randomized, double-blind, placebo-controlled, and pragmatic clinical study has been initiated to assess and evaluate ribavirin's efficacy in retorting the ongoing pandemic (NCT04581915).

Many anti-HCV drugs have been found effective against novel coronavirus SARS-CoV-2. In SARS-CoV-2 virus infection, RNA binding and replication, protein-phosphorylation, cell signaling, and antagonism of interferon pathways are executed by various non-structural viral proteins, e.g., NSP 1-14 [83] . In HCV replicative cycle, anti-HCV drugs target viral enzymes NS5A and NS5B. NS5A is endowed with pleiotropic activities and overlaps with several proteins from SARS-CoV-2, whereas HCV NS5B and SARS-CoV-2 NSP12 are RNA polymerases that share homology in the nucleotide uptake channel. Since SARS-CoV-2 and HCV are both positive-sense single-strand RNA viruses, both share the same replication mechanism [84, 85] that makes RNA-dependent RNA polymerase (RdRp) a well-established drug target.

Sofosbuvir (SFV) inhibits HCV protein NS5B [86] and is also associated with anti-viral activity against the Zika (ZIKV), yellow fever (YFV), and chikungunya (CHIKV) viruses [87] [88] [89] [90] . Gao [93] . Therefore, the combination of sofosbuvir/daclatasvir has been evaluated in many small clinical trials as a therapeutic option for COVID-19 [94] .

Galidesivir (Fig. 2) , an adenosine analog developed by BioCryst Pharmaceuticals, exhibited potent broad-spectrum activity against filovirus infections including Zika, Ebola, Yellow

Fever, and Marburg virus disease by blocking viral RNA polymerase [95, 96] . It also exhibited potent antiviral activity against other RNA virus families such as arenaviruses, bunyaviruses, paramyxoviruses, filoviruses, flaviviruses, phleboviruses, togaviruses, and coronaviruses. It is also being tested for COVID-19, and a double-blind, randomized and placebo-controlled clinical trial to evaluate its safety, pharmacokinetics and anti-viral effects against SARS-CoV-2 has been initiated (NCT03891420).

Danoprevir (Fig. 2) is a potent protease inhibitor approved in 2018 in China to treat hepatitis C. It has an IC 50 value of 0.29nM against HCV protease [97] . The first clinical trial of danoprevir combined with ritonavir has shown a promising therapeutic option for COVID-19

treatment. The clinical trial data showed that combined therapy of danoprevir and ritonavir is safe, well-tolerated and no patient had displayed composite adverse outcomes during the study [98] . However, the study was limited by the small sample size, and the results need to be corroborated in large sample studies. 

Bevacizumab is a vascular endothelial growth factor inhibitor, which has been used for the clinical management of various types of cancers, including ovarian, renal, and colorectal cancer [99, 100] . Its mechanism involves the inhibition of aberrant angiogenesis, which reduces the unusual vascular permeability and nutrients transport to cancer cells [101, 102] . Evidence has shown that hypoxia and inflammation upregulate VEGF expression in COVID-19 patients, promoting edema, vascular permeability, and eventually ARDS. A recent study has revealed that COVID-19 patients have three times higher intussusceptive angiogenesis-induced vessel growth than influenza patients in the lungs [103] . Many clinical trial studies are under process to prove its efficacy in managing COVID-19 (NCT04344782, NCT04305106, and NCT04275414).

Ruxolitinib (Fig. 3) is a potent Janus kinase (JAK) 1/2 inhibitor currently being used to treat many myeloproliferative malignancies [104] . JAK promotes immune cell activation and genetic survival programs by acting as a relay in cytokine signaling [105] . 

Toremifene (Fig. 3) is a nonsteroidal selective modulator of estrogen receptor applied in the treatment of metastatic breast cancer [106] . Toremifene is known to prevent the fusion between viral and endosomal membranes by destabilizing the envelope glycoproteins [107] . Previously, it has been reported to inhibit the viral replication against Ebola, SARS-CoV, and MERS-CoV [108] . In vivo studies further revealed the anti-Ebola activity of toremifene by inhibiting virus entry and internalization [109] . It is also known to inhibit spike protein of SARS-CoV-2 and may interact with NSP14 protein, and thus it might potentially block viral entry and replication [110] . A recent in silico study has suggested that toremifene with an anthraquinone derivative emodin combat SARS-CoV-2 effectively [111] . Emodin inhibits the ORF3a protein of SARS-CoV and blocks interaction between SARS-CoV spike protein and ACE2 receptor [111, 112] .

Carmofur or 1-hexylcarbamoyl-5-fluorouracil (HCFU) (Fig. 3) is a pyrimidine analogue and derivative of fluorouracil. It is an approved antineoplastic agent administered orally [113] and used to treat colorectal cancer [114] . It has also exhibited clinical benefits against gastric, breast, and bladder cancers [115] [116] [117] . Carmofur is a potent inhibitor of acid ceramidase (AC), promoting cancer cell survival, growth, and death [118] . Recently 

Leronlimab (Pro 140) is a humanized monoclonal antibody that targets chemokine receptors (CCR5) on the immune system's T lymphocytes [120] . It is being investigated for its efficacy in the treatment of triple-negative breast cancer (TNBC) (NCT03838367) and HIV infection (NCT03902522). Pro 140 has been reported to block HIV's entry into the cell by binding with the CCR5 receptor [121] . A recent report has shown that Pro 140 disrupts CCL5/ RANTES-CCR5 axis, restores immune homeostasis, and reduces plasma viral load in SARS-CoV-2 infected patients [122] . Moreover, it is also currently being investigated in a two-arm, randomized, double-blind, and placebo-controlled clinical study to evaluate patients' safety and efficacy with prolonged and severe respiratory illness caused by SARS-CoV-2 (NCT04678830, NCT04347239).

Selinexor (Fig. 3) is a selective inhibitor of nuclear export and an orally bioavailable anticancer drug [123] . It blocks the transport of proteins required in cancer cell growth from the nucleus to cytoplasm by binding with Exportin-1 (XPO1). This process stops cell cycle progression and results in apoptosis [124] . Selinexor can interfere with the transport of proteins that interact with SARS-CoV-2 proteins. It has been revealed that viral replication is reduced due to the blockade of nucleocytoplasmic transporter, which can sequester viral materials in the host cell nucleus [125] . Owing to these indications, Selinexor is currently being investigated in two phases II, controlled and randomized clinical trials in patients with moderate to severe cases of COVID-19 to evaluate its efficacy (NCT04355676 and NCT04349098).

eFT226 (Zotatifin) (Fig. 3) is a potent and selective eukaryotic Initiation Factor 4A (eIF4A)

inhibitor. It disrupts the assembly of the eIF4F initiation complex by promoting the binding of eIF4A to mRNA sequences. eIF4A is activated by B-cell receptor signaling and selectively upregulates oncogenes, thereby promoting cell proliferation, survival, and metastasis.

Therefore, inhibition of eIF4A by eFT226 exhibited promising anti-tumor activity in preclinical evaluation [126, 127] . Moreover, a recent study has disclosed the anti-viral activity of eFT226 against SARS-CoV-2 in vitro [128] and identified 332 protein-protein interactions between human proteins and SARS-CoV-2 based on affinity-purification mass spectrometry.

Further, the study has also identified 66 druggable targets and 69 compounds capable of targeting those targets. In this study, eFT226 emerged as a potent drug in reducing viral infectivity. These findings encourage the entry of eFT226 into clinical trials to evaluate the safety, tolerability, and plasma pharmacokinetics of eFT226. It can be used in patients with mild or moderate cases of COVID-19 (NCT04632381).

The intracellular viral trafficking depends on endocytic and exocytic cellular pathways through signal transduction, indicating that kinase inhibitors could be likely anti-viral agents by effectively blocking endocytic or exocytic pathways [129] . Many reports have shown kinase inhibitors having potent anti-viral activities in many virus-induced diseases, including coronavirus infections [130] [131] [132] [133] [134] [135] . A few of these candidates will be discussed here. 

Imatinib is a 2-phenyl amino pyrimidine derivative (Fig. 4) used as an anti-cancer drug specifically for acute lymphocytic leukemia, chronic myelogenous leukemia, chronic eosinophilic leukemia, gastrointestinal stromal tumors, hypereosinophilic syndrome, myelodysplastic syndrome, and systemic mastocytosis. It explicitly inhibits bcr-abl tyrosine kinases and other tyrosine kinases such as c-kit, PDGF-R, ABL2, and DDR1. Imatinib was reported to inhibit SARS-CoV and MERS-CoV infection in cell culture assays [133, 136, 137] .

The mechanistic study has proposed that ABL2 kinase activity is required for SARS-CoV infection. It indicates that inhibition of ABL2 with imatinib will block the fusion of coronavirus with the cell membrane [136, 137] . Since the genome of SARS-CoV-2 is highly similar to that of SARS-CoV, both the viruses use ACE2 protein as receptors to bind with host cell [42, 138] was hypothesized that imatinib might have anti-SARS-CoV-2 activity. Therefore, in several clinical trials, imatinib is evaluated to study its efficacy in treating COVID-19 patients (NCT04357613, NCT04394416, NCT04346147, NCT04356495, EudraCT2020-001236-10).

However, a recent in vitro study has shown that imatinib did not have anti-viral efficacy against SARS-CoV-2 replication [139] .

Duvelisib (Fig. 4) is a Phosphoinositide 3-kinase (PI3K) inhibitor used in the treatment of small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), and follicular lymphoma [140] . PI3K enzymes play a crucial role in regulating the cell cycle, apoptosis, DNA repair, angiogenesis, senescence, and cellular metabolism [141] . The PI3K inhibitors prevent these functions, which leads to apoptosis. It is to be noted that SARS-CoV-2 infection is associated with acute lung injury and systemic inflammatory response syndrome. Therefore, therapeutic interventions targeting pro-inflammatory agents such as chemokines and cytokines may reduce adverse inflammatory responses [142] . The preclinical results showed that duvelisib lowered pro-inflammatory cytokines in patients with lymphoma [143] . Therefore, duvelisib is currently being investigated as a treatment to reduce lung inflammation in COVID-19 patients in a phase 2 study at the Emory University Hospital (NCT04487886). The applicability of duvelisib in COVID-19 patients is due to its immune system activity but not due to its anti-cancer properties. In another phase 2 trial, the efficacy of duvelisib is being investigated as monotherapy in COVID-19 patients (NCT04372602).

Bruton tyrosine kinase inhibition protects from lethal influenza-induced, immune-induced, and sepsis-induced acute lung injuries [144] [145] [146] . Zanubrutinib (Fig. 4) , an orally bioavailable Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma [147] , is being investigated to treat COVID-19 patients. The study aims to evaluate the efficacy of zanubrutinib as supportive care to increase the survival rate by preventing respiratory failure on day 28 in hospitalized patients with COVID-19 and pulmonary distress (NCT04382586). Acalabrutinib is another second-generation Bruton tyrosine kinase inhibitor that is used for the treatment of mantle cell lymphoma [148] . Its safety, tolerability, and pharmacokinetics when coadministered with a Proton Pump inhibitor through a nasogastric tube has been investigated (NCT04497948). Ibrutinib is another Bruton tyrosine kinase inhibitor used in the treatment of B-cell malignancies and chronic graft-versus-host disease. The clinical trial observations suggest that Ibrutinib protects hypoxic patients with COVID-19 from lung injury and improves pulmonary functions [149] . A phase 2 clinical study has investigated its best dose, efficacy, and side effects (NCT04439006). Ibrutinib is expected to reduce the inflammatory response in the lungs without affecting overall immune function.

Opaganib (ABC294640) (Fig. 4) is a selective sphingosine kinase-2 (sk2) inhibitor [150] and is being investigated in clinical trials as anti-cancer drugs for advanced cholangiocarcinoma (NCT03377179) and metastatic castration-resistant prostate cancer (NCT04207255).

Opaganib also inhibits viral replication, reduces the hyper-immune inflammatory response, and minimizes ARDS-related thrombosis, which results in complications and causes fatality in COVID-19 [151] . It has been shown that sk2 is a chikungunya virus host factor co-localized with the viral replication complex [152] . It also maintains viral latency and survival in Kaposi's sarcoma-associated herpes virus [153] . The preclinical in vivo studies have indicated that opaganib reduced fatality rates from influenza virus infection [154] . Further, it downregulates the levels of TNF-alpha and IL-6 in bronchoalveolar lavage fluids and reduced ameliorated Pseudomonas aeruginosa-induced lung injury [155] . The preclinical in vivo data have indicated that opaganib has potent antiviral activity against SARS-CoV-2 by inhibiting viral replication in human lung tissue [151] . Therefore, it is being investigated in phase 2, randomized, doubleblind, and placebo-controlled study to evaluate its safety and efficacy in treating COVID-19 patients (NCT04414618).

The cell entry of SARS-CoV-2 depends on the expression of host angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2). Thus, clinically proven serine protease inhibitor could be an important medication for COVID-19

infection because these inhibitors could block the S-protein of SARS-CoV-2 required for host cell entry. Hoffmann et al. recently showed that SARS-CoV-2 also employs TMPRSS2 for SARS-CoV-2 S protein priming and S protein-driven cell entry [42] . It has also been reported that commercial serine protease inhibitor camostat mesilate inhibits TMPRSS2 in human lung

Calu-3 cells, which reduces SARS-CoV-2 infection [42] . 

Ever since ivermectin (Fig. 6 ) appeared in the late 1970s, it has become a truly revolutionary drug. It has been regarded as a 'Wonder drug' for improving the human health, nutrition, and wellbeing of billions of people [160] . It is a broad-spectrum antiparasitic and anthelmintic agent used to treat internal nematode infections, including Strongyloidiasis, Onchocerciasis, filariasis, cutaneous larva migrans, Gnathostomiasis, Ascariasis, and Trichuriasis [160] . It is also used for the oral treatment of ectoparasitic infections, such as scabies (mite infestation)

and Pediculosis (lice infestation) [160] . Ivermectin is a macrocyclic lactone, which was derived from avermectin B1. It is structurally similar to macrolide antibiotics, although it lacks antibacterial activity [161] . 

Doxycycline (Fig. 6) is a broad-spectrum tetracycline drug used as antibiotics and antiparasitics. It is often administered orally to treat chronic prostatitis, Lyme disease, sinusitis, acne, rosacea, pelvic inflammatory disease, rickettsial, gonorrhea, chlamydia, and nongonococcal urethritis [170] [171] [172] [173] [174] . It has high lipophilic property due to which it can easily permeate cells, making it quickly absorbed and highly distributed [175, 176] . Doxycycline inhibits bacterial protein synthesis by binding to 30S ribosomal subunit [176] . Since it is active against erythrocytic stages of Plasmodium falciparum, it is used to prevent and treat malaria in combination with other malarial drugs [177] . In the treatment of onchocerciasis, doxycycline targets symbiotic endobacteria Wolbachia, causing adult female worms' long-term sterility and reducing filarial nematodes [178] . Doxycycline has also been shown to inhibit dengue virus replication in Vero cells by interacting with the virus's E protein [179] . It has exhibited activity against infection of Chikungunya virus [180] . The mortality due to COVID-19 is associated with virally driven hyper inflammation and cytokine storm. Therefore, doxycycline has been suggested for the case of COVID-19 as it can significantly lower the pro-inflammatory cytokines, including IL-6 [181, 182] . It is currently in several clinical trials to manage COVID-19 in combination with other therapies (NCT04729140, NCT04715295, NCT04433078, NCT04371952).

Azithromycin (Fig. 6) [185] [186] [187] [188] [189] [190] . It has also been reported that azithromycin with hydroxychloroquine gave synergistic anti-viral activity against SARS-CoV-2 in vitro and a clinical study [191, 192] . It is evaluated in the clinical trials for combination therapy and other drugs to manage COVID-19 (NCT04334382, NCT04329832, NCT04699097, NCT04354597, NCT04359316, NCT04374903, NCT04332107).

Carrimycin, an antibiotic drug with a trade name 'Bite,' was developed in China specifically to treat upper respiratory infections [193] . It also has anti-viral, anti-inflammatory, and antifibrosis effects. In early 2020, it was reported that carrimycin could inhibit the replication of SARS-CoV-2 without causing significant side effects [194] . It has been approved for the phase 4 clinical trial. A randomized, multicentre, and open-controlled study is currently being conducted to study the efficacy and safety in treating COVID-19 patients under Beijing YouAn

Hospital's sponsorship (NCT04286503) [193, 194] .

Suramin Sodium (Fig. 6) is an anti-parasitic drug administered intravenously to treat African trypanosomiasis and onchocerciasis [195] . Suramin Sodium had also been reported to effectively inhibit the reverse transcriptase enzyme of many retroviruses, including HIV. It is also a potent therapy for various solid tumors such as prostate carcinoma and adrenocortical carcinoma and a potent inhibitor of epidermal growth factor (EGF), insulin-like growth factor (IGF-I), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumor growth factor-beta (TGF-β) [195] . A single-arm study of 20 patients with COVID-19 has been recruited to evaluate its efficacy and safety in the treatment of COVID-19.

Nitazoxanide (Fig. 6) , an antiparasitic drug nowadays recommended for treating SARS-CoV-2 infection, controls the excessive inflammatory immune response. Its bronchodilator effect and in vitro anti-SARS-CoV-2 activity have also gone for many clinical trial investigations [196] . Nitazoxanide also inhibits bovine coronavirus (L9), murine coronavirus, mouse hepatitis Kelleni et al. suggested that the combination of nitazoxanide/azithromycin could be a safer and effective regimen for the early stage of COVID-19 patients [198] . Pepperrell and his colleagues reported the clinical studies of nitazoxanide to evaluate the drug's safety. They also examined the minimum cost of drug production in the treatment of COVID-19 [199] . Authors reported that the manufacturing cost of nitazoxanide would be $1.41 for a 14-day treatment course at 500 mg BD. Moreover, at a higher dose of 1100 mg TDS, the estimated cost was $4.08 per 14-day course, equivalent to $0.29 per day. There are many clinical trials for using nitazoxanide either alone or in combination with other drugs to treat COVID-19 patients, from which some of the studies have already started recruiting patients [196] .

Chloroquine phosphate and its derivative hydroxychloroquine have been used as potential antiviral drugs [200, 201] due to their relevant anti-viral mechanism. Chloroquine phosphate can inhibit terminal phosphorylation of ACE2, whereas hydroxychloroquine promotes the pH in endosomes involved in the virus's entry [202, 203] . The early reports showed that Chloroquine phosphate inhibits SARS-CoV infection with a high in vitro activity [202, 204, 205] . Moreover, Chloroquine is a cheap and safe drug, which has been used for more than 70 years and could be a potential candidate for novel SARS-CoV-2. Recent studies showed that Chloroquine phosphate and its derivative hydroxychloroquine are also effective and showed promising results against novel SARS-CoV-2 replications [206] . 

Gautret et al. (2020) conducted a clinical trial using hydroxychloroquine (Fig. 7) in patients infected with SARS-CoV-2. The initial results show a significant reduction in the viral carriage, and the use of hydroxychloroquine was more efficient in eliminating the virus [191] . It was observed that within three to six days, hydroxychloroquine could clear viral nasopharyngeal carriage of SARS-CoV-2 in COVID-19 patients with a serum concentration of 0.46 μg/ml. The combination of hydroxychloroquine and azithromycin also showed a synergistic effect.

Liu et al. examined the anti-viral activity of hydroxychloroquine against SARS-CoV-2 infection in vitro [207] . The cytotoxicity of hydroxychloroquine was carried out in African green monkey kidney VeroE6 cells, which revealed CC50 values of hydroxychloroquine at 249.50 µM and EC 50 of hydroxychloroquine was found 4.51 µM. It has also been reported that hydroxychloroquine showed some anti-inflammatory activity and was less toxic than Chloroquine [207] .

infected Vero cells using a Physiologically-based pharmacokinetic model (PBPK) [208] . Based on PBPK models, a dose of 400 mg of hydroxychloroquine sulfate twice daily for one day and a dose of 200 mg given twice daily for four days is recommended for SARS-CoV-2 infection.

The EC 50 of hydroxychloroquine was 6.14 and 0.72 µM at 24 and 48 hours, respectively.

Sold under the brand name Eurartesim, it contains a fixed dose of piperaquine and dihydroartemisinin (Fig. 7) and generally used to treat malaria caused by Plasmodium falciparum and Plasmodium vivax [209, 210] . Under the sponsorship of the First Affiliated Hospital of Nanchang University in China, a phase 4 clinical trial has been initiated to study the efficacy of this combination in treating COVID-19 (ChiCTR2000030082).

NSAIDs are commonly used to reduce fever and muscle pain in COVID-19 positive patients, but NSAIDs for COVID-19 patients have been controversial [211, 211] . Angiotensinconverting enzyme 2 (ACE2) plays a major in COVID-19 by acting as a receptor for SARS-CoV-2, which seems to be the gateway for SARS-CoV-2 to enter the human body [212] .

Studies showed that NSAIDs like ibuprofen (Fig. 8 and half/medium (0.2 g once a day) doses of celecoxib and control groups were 100%, 82%, and 57%, respectively [216] . Celecoxib treatment also improved pulmonary opacification and pneumonia faster than the control group based on chest CT scan results. This study suggested that celecoxib may promote the recovery of mild and severe cases of COVID-19 and prevent the progression of severe disease to a critical stage. These findings may thus be indicative of the safety and efficiency of celecoxib in COVID-19 patients who have known cardiovascular conditions [216] .

Another NSAID, indomethacin (Fig. 8) , has shown potential anti-viral activity against human SARS-CoV and canine coronavirus [217] . Indomethacin does not affect coronavirus binding or entry into host cells; instead acts by blocking viral RNA synthesis. Oral administration of indomethacin markedly reduced (by 2-3 fold) shedding of canine CoV RNA in infected dogs' feces. However, this anti-viral effect was reversed upon suspension of indomethacin treatment.

Indomethacin has also been suggested to exhibit potent antiviral activity against SARS-CoV- [218] .

A recent study based on a multi-stage model-based approach showed that treatment with the sustained-release formulation of indomethacin at the dose of 75 mg twice a day is expected to achieve a complete response in 3 days of treatment in patients infected by SARS-CoV-2. It suggests that indomethacin could be considered a promising candidate for the treatment of COVID-19 [219] .

Using an original virtual screening protocol, celecoxib at 50 μM (much higher than its maximum serum concentration of 1.8 μM when 200 mg/day is used) was predicted to suppress the activity of main chymotrypsin-like protease (a key target for antiviral drugs) of SARS-CoV-2 by 12% [220] . 

A class of steroid hormones called corticosteroids (Fig. 9 ), including glucocorticoids and mineralocorticoids, are released from the adrenal cortex. The synthetic analogs of these hormones have been known as anti-inflammatory and immunosuppressive drugs, which can treat various conditions such as allergy, asthma, multiple sclerosis, septic shock, rheumatoid arthritis, and lung tissue disorders. Unfortunately, their uses are limited by the adverse side effects such as skin atrophy, osteoporosis, diabetes, glaucoma, abdominal obesity, cataracts, growth retardation, avascular necrosis and infection, and hypertension [222] . It has been proved that a COVID-19 infection results in a hyperinflammatory response which caused high mortality [223] . Therefore, corticosteroids can be used as a potent drug for diminishing lung inflammations. The EC 90 value of 6.3 μM Ciclesonide corticosteroid has been reported to block SARS-CoV-2 replication in vitro in a study on VeroE6 cells. The previous study showed that treatment of SARS and MERS patients with corticosteroids showed no improved survival but rather indicated delayed viral clearance from respiratory tract and blood associated with hyperglycemia, avascular necrosis, and psychosis [224, 225] . However, a retrospective cohort study of 201 patients with ARDS in Wuhan Jinyintan Hospital in China revealed that treatment of COVID-19 patients with methylprednisolone reduces their risk of death. However, this study was limited by a small sample size [226] . In a controlled, open-label study where 2104 patients were given dexamethasone, and 4321 patients were treated with the usual care, and it resulted in lower 28-day mortality among those receiving either oxygen alone or invasive mechanical ventilation but not among those receiving no respiratory support [227] . However, the use of corticosteroids as COVID-19 therapeutics to minimize cytokine-related pulmonary damage is controversial due to the adverse outcomes [228] .

Fingolimod (Fig. 9) is an immunomodulatory drug that modulates sphingosine-1phosphate-a receptor and inhibits lymphocytes. It is used for the treatment of relapsingremitting multiple sclerosis. The down-regulation of S1PRs reduces the egress of autoreactive lymphocytes from lymphoid tissues [229, 230] . A phase 2 clinical study to evaluate the fingolimod's efficacy was initiated, but later it was withdrawn (NCT04280588).

An immunomodulatory drug, thalidomide (Fig. 8) , is used for treating multiple inflammatory diseases, such as erythema nodosum leprosum, rheumatoid arthritis, multiple myeloma, Crohn's disease, lupus erythematosus, and prostate cancer [231] . It is also known for stimulating T cells, inhibiting cell proliferation, anti-inflammation, pulmonary fibrosis, and diminishing lung injury [232] . Previously, it has been reported that thalidomide considerably increased the survival rate, reduce the infiltration levels of inflammatory cells and chemokines (IP-10, RANTES), and cytokine (TNF-α, IL-6), and inhibited activated p-NFκB p65 in H1N1

influenza-infected mice [231] . Therefore, thalidomide may be beneficial in the treatment of COVID-19. The combination of thalidomide with a low dose of glucocorticoid could calm the patients by reducing oxygen intake and relieving the digestive system in COVID-19 patients [232] . It was also reported that the combination of thalidomide with celecoxib could reduce the cytokine storm induced by SARS-CoV-2 [233] . A Prospective, randomized, multicenter, double-blind, Placebo-controlled clinical study of thalidomide or combination of thalidomide with hormones is currently going on to assess the efficacy and safety in COVID-19 (NCT04273529, NCT04273581).

Antibodies or Immunoglobulins (Ig) are glycoprotein molecules that are produced by plasma cells. They play a significant role in the immune response by recognizing and binding to specific antigens, such as viruses or bacteria, and destroy them. Intravenous immunoglobulin (IVIG) is the antibody derived from donors to treat primary and secondary immunodeficiencies, neuroimmunological disorders, autoimmune/inflammatory conditions, and infection-related sequelae [234] . In the case of COVID-19, IVIG's anti-inflammatory functions may reduce the inflammatory response in severe SARS-CoV-2 infection and reduce the autoreactive antibodies that bind cytokines. Moreover, the IgG dimers in IVIG inhibit the activation of FcγR on innate immune effector cells [234] .

On the contrary, it has been reported that in the case of COVID-19, the function of intravenous immunoglobulin is not to boost the immune system but to suppress a hyper-immune response.

It takes place via its immunomodulatory effect [235] . However, the current randomized, double-blinded, placebo-controlled phase 3 clinical trials focus on understanding its efficacy and safety in COVID-19 patients (NCT04261426, NCT04350580, NCT04411667, NCT04400058).

Interferons (IFNs) are a class of cytokines that can inhibit bacterial and viral infections and neoplasia which can be divided into two classes as type I (IFN-α and IFN-β) and type II (IFN-γ) [236] . It has been used to treat many viral infections such as Hepatitis B and C virus control multiple sclerosis [237] [238] [239] . A placebo-controlled, double-blind clinical trial conducted in the UK revealed that hospitalized non-ventilated COVID-19 patients treated with interferon beta-1a for 14 days (once daily) probably recovered due to ambulation without restrictions, had less chance of developing severe disease, and had reduced breathlessness, in comparison with a placebo-controlled group [240] . A randomized, open-label, Phase 2 clinical trial evaluated the efficacy and safety in treating COVID-19 patients by combining Interferon Beta-1b, Ribavirin, and Lopinavir/Ritonavir showed reduced viral load and reduced the mortality rate in the combination therapy group than in the control group. The patients treated with combined therapy had more remarkable clinical improvement, sequential organ failure assessment, and shorter hospital stay [240] . In a retrospective cohort study in China, 77 moderate COVID-19 patients were treated with nebulized interferon alfa-2b or with the combination of nebulized interferon alfa-2b and umifenovir or umifenovir alone. The result showed the reduced systemic inflammation and shorter time for viral clearance in the upper respiratory tract on treatment with interferon alfa-2b than in the treatment with umifenovir, only [240] . In another randomized, double-blind, placebo-controlled phase 2 study with nebulized interferon beta-1a in 101 COVID19 adult patients revealed that it showed considerably higher odds of clinical improvement across the WHO Ordinal Scale for Clinical Improvement than those who received placebo [241] .

Interleukins are a group of cytokines that signal specific cells to regulate the immune systems.

They facilitate communication among the immune system cells, regulate transcription factors, and control cell differentiation, proliferation, inflammation, and antibody secretion [242, 243] .

The pro-inflammatory cytokine IL-2 is secreted by Th-1 cells, which credibly participates in T Cells activation to produce TNF-α and IFN-γ. IL-2 is known for promoting the cytolytic activity of natural killer cells (NK). Thus, the therapeutic applications to stimulate the immune system are supposedly beneficial in COVID 19 patients [244, 245] . A phase 1 clinical study has shown the higher production of CD4+ T, CD8+ T, and NK cells in COVID-19 infected patients when treated with a low dose of IL-2 intramuscularly (ChiCTR2000030167).

Although lesser clinical evidence is available to support traditional medicines' efficacy in the treatment of COVID-19, its use seemed to be one of the viable methods during this time of crisis. During the SARS epidemic in 2003, China used traditional Chinese medicines and standard medicines to treat around 40-60% of SARS-infected patients [246] . The Chinese traditional medicines helped control the fever, cleared chest infection faster, reduced the need for consumption of steroids, and gave relief from other symptoms [247] . Further, it has also been used in the treatment of H1N1 influenza during its outbreak. The high similarity in pathogenesis, genomics, and epidemiologic between SARS-CoV-2 and SARS-CoV has encouraged traditional medicines to treat COVID-19 [247, 248] . Based on the overall symptoms and treatment results of COVID-19, traditional Chinese medicines have been advised to prescribe traditional medicines such as qingfei paidu decoction (QPD), sheganmahuang decoction, gancaoganjiang decoction, qingfei touxie fuzheng recipe, etc. [249] .

Both the Chinese and the South Korean guidelines have recommended the Qingfei Paidu decoction to treat COVID-19 patients [250] . [249] . According to the recent report, this herbal formula targets the lungs and spleen in COVID-19 patients, thereby elevates immunity and lowers inflammation [250] . The traditional Chinese medicine formula called Lianhuaqingwen has been reported recently to inhibit SARS-CoV-2 replication on Vero E6 cells significantly and remarkably lowers proinflammatory cytokines (IL-6, TNF-α, CXCL-10/IP-10, and CCL-2/MCP-1) production at mRNA level [251] . However, the exact molecular mechanisms of traditional medicines are unknown and more evidence will be required to conclude its efficacy.

Although there is no conclusive evidence for the treatment of COVID-19 using Ayurvedic medicine, some of the proven herbal immunomodulatory medications can be employed to thwart its symptoms [252] . The Council of Scientific and Industrial Research (CSIR) and the AYUSH ministry have collaboratively initiated clinical trials to validate Ayurvedic herbs' formulation to treat COVID-19. They are Ashwagandha, Guduchi +Pippali Yashtimadhu, and a polyherbal formulation (AYUSH-64) [253, 254] . The compositions of AYUSH-64 are stem bark of Alstonia scholaris, roots of Picrorhiza kurroa, Swertia chirata, and the seed of Caesalpinia crista [255] . They have also initiated a clinical study comparing the effectiveness of Hydroxychloroquine with Ashwagandha (Withania somnifera) in health care workers [253, 256] .

The studies have shown that the ingredients of AYUSH-64 exhibited immunomodulatory and anti-inflammatory activities. The in vivo studies showed that total alkaloids from Alstonia scholaris suppress the production of inflammatory cytokines IL-8 and TNF-α in bronchoalveolar lavage fluid (BALF) and lungs [257, 258] . Swertia chirata is a potent inhibitor of NF-kB/DNA interactions and suppressing pro-inflammatory IL-8 expression in cystic fibrosis cells. Further, xanthones from Swertia chirata have the potential to inhibit COX-2 and suppress the production of pro-inflammatory cytokines IL-6 and TNF-α [259] . In vitro study using Swertia chirata extracts has also shown anti-viral activity against type-1 Herpes simplex virus (HSV). [260] Moreover, the Swertia chirata plant inhibited the expression of viral protein (Vpr) in Hela cells harboring the TREx plasmid encoding full-length Vpr (TREx-HeLa-Vpr cells) [261] . The seed extracts of Caesalpinia crista increase antibody production in rats demonstrating favorable immunostimulant properties. It also displayed anti-inflammatory, analgesic, and antipyretic activities [262] [263] [264] .

The SARS-CoV-2 pandemic continues to spread worldwide, and more than 118 million people have been infected, and the lives of over 2.6 million people have been lost. This pandemic calls for the urgent and rapid development of effective therapeutics and vaccines within a limited time. Although extensive research has been carried out since the pandemic began, no effective therapeutic drugs have been discovered or developed as yet. A COVID-19 vaccine may be the best defense against SARS-CoV-2, but there is no guarantee that vaccines will protect a hundred percent of the people. Moreover, the virus has a high mutation rate; therefore, it is uncertain that the vaccine prepared against one strain will protect against other mutated strains of SARS-CoV-2. For instance, a new strain of SARS-CoV-2 detected in the UK has a high transmission rate due to genetic mutation in the spike protein. Therefore, in addition to the vaccines, the focus of research on developing effective drugs for the therapy of COVID-19 should be emphasized. Moreover, the viral disease outbreak will not end with the COVID-19 pandemic. Thus any anti-viral therapeutic development will add potent armors to the fight against viral disease outbreaks in the future.

Although the development of small-molecule inhibitors against SARS-CoV-2 is an alternative solution, its application has many limitations for targeted therapies. The adverse side effects are often associated with small molecule inhibitors as their competitive inhibition behavior often leads to off-target activities. Moreover, prolonged exposure to small molecule inhibitors can also influence the mutation of target proteins, which may give rise to drug resistance [265] .

Further, prolonged inhibition may promote compensatory protein overexpression and protein accumulation, thereby depleting the target protein only partially and causing incomplete suppression of downstream signaling pathways. Therefore, a new technique called induced protein degradation, such as proteolysis-targeting chimeras (PROTACs) can be exploited to enhance the drug compounds' antiviral activity against SARS-CoV-2. PROTACs will perform specific inhibition and degrade the viral targets and might increase the potency by many folds.

A recent study showed that PROTACs developed against HCV protease reduced susceptibility to resistance mutations [266] . The development of PROTAC can be done by selecting a feasible target protein of SARS-CoV-2, such as E protein, responsible for viral replication. The E protein lacks glycosylation, and thereby, the protein epitopes are not shielded by large sugar moieties, making binding of small molecules easier. Targeting E protein has emerged as a potent anti-viral strategy to develop inhibitors for coronaviruses such as SARS. Disruption of E protein can lead to virulence and affect viral assembly, morphology, and secretion.

Herbal medicines and natural products have good credentials for being prophylactic in many diseases, including respiratory infections. Therefore, in this global crisis, exploring different herbal medicines to derive effective prophylactics from treating COVID-19 is a promising approach. Effective herbal products for COVID-19 treatment should be based on scientific rationale and well-planned research. Their efficacy can be enhanced by producing synthetic derivatives of the bioactive compound present in them.

In summary, the international collaboration, vaccination, and more focused research in developing potent anti-viral drugs for SARS-CoV-2 is presumably the way forward for combating SARS-CoV-2 effectively.

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Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines

Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2)

A review on scope of immuno-modulatory drugs in Ayurveda for prevention and treatment of Covid-19

Formal launch of the inter-disciplinary studies involving AYUSH interventions for COVID 19 situation. pib.gov.in/Pressreleaseshare.aspx?

Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice

Effect of total alkaloids from Alstonia scholaris on airway inflammation in rats

Expression of Pro-inflammatory Interleukin-8 is Reduced by Ayurvedic Decoctions: INDIAN DECOCTIONS REDUCE IL-8 EXPRESSION

Antiviral activity of the Indian medicinal plant extract, Swertia chirata against herpes simplex viruses: A study by invitro and molecular approach

Viral protein R inhibitors from Swertia chirata of Myanmar

In vivo immunomodulatory activities of the aqueous extract of bonduc nut Caesalpinia bonducella seeds

In vivo anti-inflammatory, analgesic and antipyretic activities of a medicinal plant, Caesalpinia bonducella F

Studies on antiinflammatory, antipyretic and analgesic properties of Caesalpinia bonducella F. seed oil in experimental animal models

A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agents

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

The authors are grateful to the Department of Chemistry, Mizoram University, Aizawl, India, for providing the necessary facilities. Jayanta Dowarah acknowledges the DST for Inspire fellowship. Brilliant N. Marak acknowledges the MoTA for the NFST research fellowship.

The authors declare no conflict of interest.

Dear Editor, I am submitting manuscript entitled "Potential drug development and therapeutic approaches for clinical intervention in COVID-19" for publication in your esteemed journal. The present manuscript is not submitted and published in any other journal. There is no conflict of interest. The list of authors is as under 1