Journal of Environmental and Public Health
Volume 2021 (2021), Article ID 6631721, 11 pages
https://doi.org/10.1155/2021/6631721

Review Article

Drug Repurposing Approach, Potential Drugs, and Novel Drug Targets for COVID-19 Treatment

Zemene Demelash Kifle,¹ Akeberegn Gorems Ayele,² and Engidaw Fentahun Enyew³

¹Department of Pharmacology, School of Pharmacy, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
²Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia
³Department of Human Anatomy, School of Medicine, College of Medicine and Health Sciences, Gondar, Ethiopia

Correspondence should be addressed to Zemene Demelash Kifle; ppharma737@gmail.com

Received 20 October 2020; Revised 23 February 2021; Accepted 17 April 2021; Published 22 April 2021

Academic Editor: Felix Broecker

Copyright © 2021 Zemene Demelash Kifle et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.

1. Introduction

COVID-19 virus belongs to a family of viruses that can cause various symptoms, including fever, breathlessness, pneumonia, and pulmonary infections [1]. On 29 December 2019, the WHO used the term 2019 novel coronavirus or 2019-nCoV to refer to coronavirus in Wuhan, China, that attacks the lower respiratory tract of patients with pneumonia [2]. Later on, February 11, 2020, WHO gave an official name as coronavirus disease 2019 abbreviated as COVID-19. In this name, “CO” stands for “corona,” “VI” for “virus,” and “D” for the disease [3, 4]. As of October 2020, over 39,262,512 cases of COVID-19 have been documented worldwide with nearly 1,104,206 deaths, and 29,423,118 were recovered [2, 5].

Regarding its features, coronavirus is an enveloped ribonucleic acid (RNA) virus, from the genus betacoronavirus, that is distributed in birds, humans, and other mammals [6]. Coronavirus comprises four subfamilies: delta, gamma, beta, and alpha coronaviruses. Among these subfamilies, alpha- and betacoronavirus originate from mammals, specifically from bats; gamma- and delta-viruses originate from pigs and birds [3]. Coronavirus has a single-stranded RNA genome that is enclosed with an enveloped structure and the shape is either spherical or pleomorphic [6].

Different viral agents are linked to an increased risk of more severe disease course and respiratory complications in immune-compromised patients [7]. Even though several investigations have been done on the treatment of COVID-19 in different parts of countries, there is a lack of reviews that comprehensively express novel targets for the management of COVID-19 infection in a different country. Thus, this review summarizes the roles of existing drugs, potential drugs, and novel drug targets for COVID-19 treatment.

2. Drug Repurposing for COVID-19

Currently, several vaccines and therapeutic agents are in use for COVID-19 infection prevention and treatment. Vaccines such as Pfizer/BioNTech, Moderna, Johnson & Johnson’s Janssen, AstraZeneca are authorized and recommended for COVID-19 infection prevention [8–10].

The whole world is worrying about COVID-19 infection due to the lack of adequate care and public health emergencies. Several governmental and nongovernmental organizations are making exertions to offer COVID-19 patients with quarantine and rapid diagnosis, along with studies to find an appropriate cure that can monitor and avoid the current dangerous effects of the disease [11]. Efforts are made from the day that the virus has erupted which includes drug repurposing and others. Drug repurposing or repositioning is an auspicious field in the development and discovery of therapeutic agents that identifies new therapeutic options for existing drugs [11, 12]. Several established antiviral medications, formerly discovered or used in the management of malaria, MERS, and SARS are being tested for COVID-19 treatment and some of them are being used in clinical trial treatments for COVID-19 infection [13]. This narrative summarizes the current evidence of major potential COVID-19 therapies, repurposed or new drugs, and offers an overview of current clinical practice and recommendations for this new coronavirus pandemic treatment.

2.1. RNA-Dependent RNA Polymerase Inhibitors

Among the most fascinating and exciting drug targets for SARS-CoV-2 are the RNA-dependent RNA polymerase (RdRP) and a viral enzyme for viral RNA replication in host cells. Since RdRP is a viral enzyme without host cell homologs, it is possible to produce selective SARS-CoV-2 RdRP inhibitors that have increased potency and fewer off-target effects. Two such nucleoside analogs, remdesivir and favipiravir, are currently being tested in clinical trials for the management of hospitalized COVID-19 infected patients [14].

A recent study has revealed that remdesivir is a potential agent for the treatment of COVID-19 [15]. Remdesivir produces its effect by inhibiting the RNA polymerase and integrating it into nascent viral RNA. This leads to two important outcomes such as termination of the viral RNA chain and subsequently inhibits the viral genome replication. The previous finding revealed that remdesivir was not effective for the treatment of Ebola. However, it provides the safety of remdesivir in humans, which permitted the remdesivir clinical trial in the treatment and protection of COVID-19 without delay [16]. According to an in vivo study in mice, the treatment of MERS-CoV infected mice with remdesivir revealed a reduction in lung viral load, recovery of lung function, and reduce in lung tissue damage [17]. Similarly, both in vivo and in vitro studies showed promising activity of remdesivir in the treatment of SARS-CoV and MERS-CoV [18].

Favipiravir is a prodrug that requires conversion to its active form by phosphoribosylation [19]. Favipiravir became a therapeutic agent that showed a promising effect and is agreed for the management of novel influenza on February 15, 2020, in China. At the very epicenter of the pandemic, favipiravir was initially used for the treatment of SARS-CoV-2 in Wuhan. This medication was then approved for emergency use in Italy as the pandemic spread to Europe and later on to many other countries including Moldova, Ukraine, Japan, Uzbekistan, Kazakhstan, and Russia. The latest commercial launches have also occurred in Egypt, Bangladesh, and Turkey. Favipiravir also obtained approval from the Drugs Controller General of India for mild and moderate COVID-19 infections in India in June 2020 [20]. Case-control studies showed that patients who received favipiravir at a faster rate than those who did not have reduced symptoms of pneumonia and fever [19].

Sofosbuvir and daclatasvir are direct-acting antiviral agents against hepatitis C [21]. They have predicted in silico activity against SARS-CoV-2 [22, 23] and therefore are attractive treatment options. In a recent study, sofosbuvir and daclatasvir demonstrated in vitro activity against Huh-7 and Calu-3 cells infected with SARS-CoV [24]. The study also revealed that daclatasvir is effective against in vitro 6 infected cells; however, sofosbuvir does not. Reports of neurological complications associated with COVID-19 are increasing [25, 26]. And sofosbuvir demonstrated protective activity against SARS-CoV-2 infected brain organoids [27].

2.2. Ebselen

Ebselen has been previously found to exhibit potent antiviral activity against many viruses including human immunodeficiency virus type 1 (HIV-1) [28], hepatitis C virus (HCV) [29], influenzas A virus [30], and Zika virus [31].

Ebselen has also shown an effect in rescuing liver injury induced by chemical and microbial stimuli [32]. One of the most common findings observed in severe cases of COVID-19 is liver injury [33]. Therefore, treatment with ebselen might add benefits to this particular aspect of the disease. Moreover, ebselen is also found to be effective in managing focal ischemic injury by decreasing IL-6 [34], which can protect SARS-CoV-2 infected patients with venous thrombosis and vascular injury [35]. Nevertheless, the findings of these previous studies give us hope for the therapeutic potential of ebselen in managing COVID-19. Further investigations are required using randomized clinical control trials before they can be included in any treatment regimen. Ebselen already possesses antiviral activity against several viruses and exhibits potent antiviral activity against SARS-CoV-2 via Mpro inhibition [36], repurposing it for SARS-CoV-2 treatment seems to be a reasonable option [37]. Therefore, ebselen can be considered as a potential therapeutic candidate for COVID-19 patients. However, before including it in the treatment guidelines and widespread use as a potential antiviral drug, further studies should be undertaken to establish its efficacy using experimental and clinical studies [38].

2.3. Arbidol

Arbidol is a broad-spectrum inhibitor of parainfluenza virus, influenza A and B virus, and other viruses such as the hepatitis C virus [39]. Arbidol is an orally administered drug at a dose of 200 mg for adults, 3 times/day for no more than 10 days [40]. A recent finding showed that arbidol has the potential to inhibit COVID-19 infections/SARS-CoV-2 infection at 10–30 μM concentration. Arbidol has played a preventive role among health professionals as evidenced by the uninfected rate of health care workers in the arbidol which was significantly higher than that of individuals in the nonarbidol group [41]. Arbidol can also induce interferon and immune cells and therefore has a synergistic therapeutic effect against coronavirus when combined with interferons [42].

2.4. Interferons

Interferons are a cytokine family that have antiviral properties. Since it possesses antiviral activity tested in both in vivo and in vitro models, it has been wished for as a possible therapeutic agent for the management of COVID-19 infection. The functions as a paracrine as well as autocrine manners to induce the expression of various interferon-stimulated genes that provide antiviral effects to the host cells [43]. Among interferons, interferon-α is known to have broad-spectrum antiviral activity. Following activation, multiple effects can be detected including induction of gene transcription. It also inhibits cellular growth, alters the state of cellular differentiation, interferes with oncogene expression, alters cell surface antigen expression, increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells. Interferon-α is used to treat hepatitis, though it is reported to inhibit SARS-CoV replication. In vitro test revealed that interferon-α is only partially effective against coronavirus [44].

2.5. Protease Inhibitor

Medications that are effective against different RNA viruses are being candidates for the treatment of severe acute respiratory syndrome virus 2. As far as this is concerned, the most familiar medications tried in patients infected with severe acute respiratory syndrome virus 2 are IFN, lopinavir/ritonavir, ribavirin, and some others [45]. The protease enzyme is responsible for the proteolytic processing of polyproteins and is required for the virus to replicate within host cells. Lopinavir along with its booster drug, ritonavir, is known for the management of human immunodeficiency. Because of the effective treatment of MERS, the feasibility of the combination of lopinavir/ritonavir was stated in the most recent guideline for the management of COVID-19 infection. Data from in vitro studies revealed that lopinavir/ritonavir can restrict coronavirus replication [46]. Previous studies revealed that lopinavir and ritonavir are capable of inhibiting the 3CL1 proprotease of COVID-19 viral infection [47, 48]. Moreover, several in vivo and in vitro studies revealed the effectiveness of these antivirals for the treatment of MERS and SARS viruses [49, 50]. Recently, the coformulation of lopinavir/ritonavir was tested in patients infected with COVID-19 infection, though it exhibited a slight advantage for improving the clinical outcome of patients infected with COVID-19 [50, 51].

2.6. Ivermectin

Ivermectin exerts broad-spectrum antiviral activity against several animal and human viruses, including both RNA and DNA viruses. The antiviral potential of ivermectin against various viruses is mediated by targeting importin α/β-mediated nuclear transport of HIV-1 integrase and NS5 polymerase; NS3 helicase; nuclear import of UL42; and nuclear localization signal-mediated nuclear import of Cap. As SARS-CoV-2 is an RNA virus, the antiviral activity of ivermectin may be mediated through the inhibition of importin α/β-mediated nuclear transport of viral proteins. The clinical efficacy and utility of ivermectin in SARS-CoV-2-infected patients are unpredictable at this stage, as we are dealing with a completely novel virus [52]. Targeting the viral nuclear transport process could be a potential treatment modality for RNA viruses including COVID-19 since the viral nuclear transport process plays a significant role in the embarrassment of the host’s antiviral response and enhancing the viral replication cycle [53].

2.7. Melatonin

Melatonin is a hormone secreted from the pineal gland in a 24-hour circadian rhythm, regulating the normal sleep/wake cycle. As a supplement, melatonin has both phase-shifting and sleep-promoting properties. In addition to promoting sleep, the physiologic roles of melatonin include regulation of the secretion of growth hormone and gonadotropic hormones. It also possesses antioxidant activity. Recently, melatonin is being a potential agent in the treatment of viral infections. Leukocyte-secreted melatonin exerts a strong immune-modulatory role [54, 55]. Previous studies revealed that an increase in age is a weak prognostic factor in patients with COVID-19 infection. This is because, in advanced age, both physiological functions and immune responses are diminished as a consequence of age in the elderly; they have more chances to develop serious pneumonia secondary to COVID-19 infection [56]. In the previous study, melatonin has shown a key role in attenuating and preventing the cytokine storm, leading to a reduction in mortality and morbidity which is due to COVID-19 infection [57].

2.8. Teicoplanin

Teicoplanin is a glycopeptide antibiotic with a spectrum of activity. It is similar to vancomycin but some coagulase-negative staphylococci are less sensitive to teicoplanin than to vancomycin. Recently, teicoplanin showed significant activity against SARS-CoV through in vitro model. Thus, teicoplanin can serve as a potential therapeutic agent for the treatment of COVID-19 [58]. Teicoplanin has been effective against numerous virus types including SARS-CoV, MERS-CoV, flavivirus, HIV, Ebola, Ebola, and influenza virus [59, 60]. Teicoplanin inhibits the virus replication cycle and the release of viral RNA by acting on the early step of the viral life cycle (constraining the low pH cleavage of the viral spike protein). This activity indicates the target sequence that serves as a cleavage site for cathepsin L is conserved among SARS-CoV spike protein [58]. Teicoplanin at a concentration of 1.66 μM can inhibit 50% of the virus (in vitro), which was lesser than the concentration reached in human serum (8.78 μM) [58].

2.9. 5-Alpha Reductase Inhibitors

Finasteride and dutasteride are the two main 5-alpha reductase inhibitors used in clinical practice and studied for safety and effective profile in the long run [61–63]. The rationale for their use is based on the blockage of conversion of testosterone into 5alplha-DHT and mitigation of transmembrane protease, serine 2 (TMPRSS2) expression [64–66], eventually hampering the overrepresentation of males, and particularly bald ones, in severe COVID-19. Their benefits may be exhibited if used as a preventive strategy or during the first stage of COVID-19 and have demonstrated correlations with lower severity, although causality could not be established [67, 68]. There is one clinical trial currently testing dutasteride in COVID-19 [69].

2.10. Spironolactone

Spironolactone, a safe antihypertensive and antiandrogenic drug used since 1959 that acts as a potassium-sparing diuretic drug by antagonizing mineralocorticoid receptors, tends to disclose favorable patterns of the RAAS and ACE2 expression, reduces TMPRSS2 activity due to its antiandrogenic activity, and may prevent acute lung injuries due to its pleiotropic effects [70, 71].

Among therapeutic targets for SARS-CoV-2, a long-used and safe mineralocorticoid and androgen receptor antagonist, with eﬀective antihypertensive, cardioprotective, nephroprotective, and antiandrogenic properties may oﬀer pleiotropic actions in diﬀerent sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balanced membrane-attached and free circulating ACE2 and between angiotensin II and angiotensin (1–7) (Ang-(1–7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may protect SARS-CoV2 and has suﬃcient plausibility to be clinically tested, particularly in the early stages of COVID-19 [70].

2.11. Sildenafil/Tadalafil

The PDE5 inhibitor sildenafil citrate is a vasodilator that was approved in 1998 for treating erectile dysfunction and more recently received an indication for pulmonary arterial hypertension and idiopathic pulmonary fibrosis [72]. Sildenafil is currently under investigation in a phase 3 trial in patients with COVID-19 (NCT04304313), which will help clarify its therapeutic potential [73]. The goal of sildenafil treatment is to prevent or perhaps block the progression of fibrosis and to improve respiratory parameters in patients. Tadalafil has also shown PDE5 inhibition with an IC₅₀ of 5 nM. It possesses high selectivity for PDE5 over PDE1–4 and PDE6. In particular, tadalafil is more selective against PDE5 than PDE6, whereas sildenafil shows similar potency to inhibit PDE5 and PDE6 [74]. Theoretically, the once-daily use of tadalafil, which is a long-acting drug, could be useful to improve tissue vascularization and to combat fibrosis. Tadalafil is probably less effective in the acute phase but could lend itself to use once daily for possible prevention in patients with erectile dysfunction who are not interested in sexual activity, and for similar purposes, it could be administered to all discharged patients recovering from COVID-19 [75].

2.12. Statins

Statins are known for their pleiotropic anti-inflammatory effects, including augmentation of ACE2 expression and inhibition of the Toll-like receptor- (TLR-) MYD88-NF-kB pathway in vitro [76]. In COVID-19 patients, the same anti-inflammatory activity might improve outcomes in those patients with increasingly severe illness, worsening respiratory failure, and increasing D-dimer and IL-6 levels: all factors associated with increased mortality [77, 78]. Earlier studies suggested the possible effectiveness of statin therapy in decreasing influenza-related hospitalizations and deaths. During the 2009 H1N1 pandemic, statin therapy was associated with reduced disease severity among hospitalized patients [79–82]. Because of their pleiotropic actions, statins have been purposed to reduce the occurrence and severity of acute respiratory distress syndrome states and the effects of endotoxin in lung injury [83,84], acting against COVID-19, particularly in the second and third stages [85, 86].

2.13. N-Acetylcysteine

N-Acetylcysteine (NAC), a precursor of the antioxidant glutathione, has been used to loosen thick mucus in the lungs and treat acetaminophen overdose for decades. It also boosts the immune system, suppresses viral replication, and reduces inflammation. Despite these valuable features, NAC has been mostly overlooked throughout SARS-Cov and MERS-Cov epidemics, as well as the current COVID-19 pandemic [87].

NAC has been demonstrated to inhibit NF-κB, as well as the replication of human influenza viruses (H5N1, Vietnam/VN1203 strain) in human lung epithelial cells in a dose-dependent manner (5 to 15 mM). It also reduced the production of proinflammatory cytokines (IL-8, CXCL10, CCL5, and IL-6), thus decreasing the chemotactic migration of monocytes [88]. In addition, NAC has also been shown to inhibit replication of other viruses, such as human HIV [89], and respiratory syncytial virus (RSV) [90]. This means that, theoretically, NAC has the potential to inhibit SARS-Cov-2 as well because of its ability to negatively regulate NF-κB [87].

2.14. Bromhexine Hydrochloride

Bromhexine hydrochloride is approved in many countries as a commonly used over-the-counter expectorant for both adults and children and has been marketed since 1963 [91, 92]. It is characterized by low side effects and relatively low cost [93]. Considering all these characteristics, bromhexine hydrochloride could be an ideal candidate as a potential COVID-19 treatment [93, 94].

According to the results of cell experiments, the IC₅₀ of bromhexine hydrochloride on TMPRSS2 protease is 0.75 μM, and the target cell concentration is about 308.62 ng/mL [95]. The pharmacokinetic data for oral bromhexine hydrochloride show that the adult maximum blood concentration (Cmax) with oral administration of 8 mg bromhexine hydrochloride is 22.50 ± 7.50 μg/L [96], and the concentration in the parenchymal tissue of the lung is 54–132.75 ng/mL, far less than the concentration of target cells [91]. Because the new pharmacokinetic parameters of bromhexine hydrochloride are proportional to an oral dose of 8–32 mg [96], the pulmonary concentration with 32 mg of the drug would be 216–531 ng/mL (median 373.5 ng/mL), which could achieve the target cell concentration to inhibit TMPRSS2. In adults, Yong et al. suggested an oral dose of bromhexine hydrochloride up to 96 mg per day in clinical practice [97], to maximize the drug concentration in blood. We did not find reports of pediatric use experiences [98].

2.15. Chloroquine Phosphate or Hydroxychloroquine

Chloroquine (CQ), an old antimalarial agent with anti-inflammatory and immunomodulatory activities, has gained significant interest as a potential therapeutic option for the management of COVID-19 associated pneumonia in multicenter clinical trials conducted in China. In early February, Wang et al. demonstrated potent in vitro activity of chloroquine against SARS-CoV-2 with an EC₅₀ at 48 hours of 1.13 μM in Vero E6 cells. As an alternative, hydroxychloroquine (HQ), a compound that differs from chloroquine only by a single hydroxyl group, has garnered interest. It is perceived as having better tolerability than chloroquine, which has led to long-term usage in rheumatological disorders [3, 99]. These data were consistent with previous data for chloroquine’s inhibitory activity against SARS-CoV-1 and MERS-CoV in various cell lines, where EC₅₀ values of 1–8.8 and 3.0 μM were demonstrated, respectively. Chloroquine and hydroxychloroquine have a long-standing history in the prevention and treatment of malaria and the treatment of chronic inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis [100].

Previous studies reported that CQ/HCQ possess a broad spectrum of antiviral effects on a variety of viruses as diverse as (HIV) Marburg virus, Zika virus, dengue virus, Ebolavirus, and SARS-CoV-1. CQ and HCQ can interfere with the binding of viral particles to their cellular cell surface receptor or the pH-dependent endosome-mediated viral entry of enveloped viruses to inhibit the viral cycle. They can also interfere with the posttranslational modification of viral proteins or impair the proper maturation of viral protein by pH modulation. In addition, CQ and HCQ can regulate the immune system by affecting cell signaling and the production of proinflammatory cytokines [101]. Moreover, CQ on the growth of SARS-CoV-2 in vitro and an early clinical trial conducted in COVID-19 Chinese patients showed a significant effect, in terms of both clinical outcome and viral clearance. Chinese experts recommend that patients diagnosed with mild, moderate, and severe cases of COVID-19 pneumonia and without contraindications to it be treated with 500 mg chloroquine twice per day for ten-day treatment duration. HCQ (an analog of chloroquine) has been demonstrated to have an anti-SARS-CoV activity in vitro. Its clinical safety profile is better than that of CQ (during long-term use) and allows higher daily dose and has fewer concerns about drug-drug interactions. HC/HQ alone and in combination with azithromycin was highly effective in clearing viral nasopharyngeal carriage within six days in COVID-19 subjects [102].

2.16. Corticosteroids

Corticosteroids have been used for SARS-CoV-1 and MERS-CoV infections in a few studies. The use of corticosteroids drugs for these viral infections including influenza A had been associated with decreased mortality. But their use now became controversial because of their effect on the suppression of the immune system. Though, patients with COVID-19 infection taking corticosteroids for long-term maintenance dose did not show increment in the incidence of development of severe or critical pneumonia. Meta-analysis studies showed that among corticosteroids, dexamethasone, methylprednisolone, hydrocortisone, and prednisolone were tested for their role in the management of COVID-19 infection [103]. A study conducted in UK showed that dexamethasone has effectively decreased deaths by 1/3 in patients infected with COVID-19 [104]. Similarly, a study conducted on hospitalized patients revealed that the mortality rate of COVID-19 infected hospitalized patients was significantly () varied reliant on respiratory support. Dexamethasone showed a reduction in deaths by 1/3 in patients getting invasive mechanical ventilation (, 29.00% vs. 40.70%), by 1/5 in patients getting oxygen without invasive mechanical ventilation (, 21.50% vs. 25.00%). However, dexamethasone did not decrease mortality in patients not getting respiratory support (, 17.00% vs. 13.20%) [105]. The mechanism behind corticosteroids in COVID-19 remains to be an objective of ongoing clinical trials [106]. However, their anti-inflammatory effect can decrease systemic inflammation, reduce fluid accumulation in the lung tissue, and prevent more alveolar damage from spreading, thus improving hypoxia and decreasing the risk of respiratory failure [107].

3. Targets for New Drug

Since the available drugs are not much successful for COVID-19, a search for new drug/drug targets is underway. Therefore, the following are major sites based on molecular targets [108].

3.1. Blocking Coronavirus Structural Protein

The SARS-CoV-2 (SARS-CoV-2S) surface spike glycoprotein plays a significant role in viral infection, beginning with the identification of the host cell surface receptor and binding the viral envelope to the host cells for fusion and infiltration. Spike glycoprotein includes host receptors for ACE2 for entry into host cells, where spike receptor recognition and attachment are recognized and attached [109]. F26G19, CR3014, S230, CR3022, and F26G18 are recently developed therapeutic antibodies for the management of COVID-19 infection that target spike-protein [110].

3.2. Targeting Viral Enzyme

The main protease, 3C-like protease (3CL (pro)), and papain-like protease (PLpro) are drug targets among coronaviruses [111]. By identifying the P1 and P1–P4 sites, 3CLpro cleaves 11 sites in the polyproteins, with the recognition sequence Leu-Gln (Ser, Ala, Gly), including its N- and C-terminal autoprocessing sites. A recent study has shown that through the subsite cooperation of Phe P2 and Phe P3 P3, 3CLpro cleaves its C-terminal autoprocessing site. On the other hand, PLpro is involved as an evasion mechanism against host antiviral immune responses in cleaving posttranslational protein modifications on host proteins [49]. Therefore, in the processing of polyproteins and viral replication, both PLpro and 3CL (pro) play important roles and they are a potential target. Therapeutic agents such as cyclohexyl methyl (IC₅₀ = 0.71 μM), α-Ketoamide inhibitors (IC₅₀ = 11.4 ± 1.4 μM), pyrazolone derivatives (IC₅₀=5.8 ± 1.5 μM), and 1,3,4-oxadiazole disulfide (0.516 ± 0.06 μM) have shown a significant in vitro SARS-CoV-2 inhibitory activities by targeting 3CL(pro) protease. [49].

Unlike that of 3CL (pro)), targeting the PLpro is found to be challenging for pharmaceutical companies that scramble to discover a drug against COVID-19. The encounter behind this is that PLpro recognizes the C-terminal sequence of ubiquitin of both the virus and host which in turn inhibits host-cell deubiquitinases and lacks selectivity [112].

3.3. Dipeptidyl Peptidase 4 as a Target

Dipeptidyl-peptidase 4 (DPP4) is a glycoprotein of 110 kDa and is expressed on the surface of a variety of cells. DPP4 has a role as a peptidase, cutting N-terminal dipeptides, leading to degradation of several compounds such as dipeptides from a variety of substrates, including neuropeptides, growth factors, incretin hormones, and cytokines [113]. DPP-4 is expressed on cells inside such as interstitial (endothelial cells), type I and II cells (lung parenchyma), mononuclear lymphoid cells, and macrophages cells. Moreover, increased DPP4 immunostaining in alveolar macrophages, alveolar epithelial, and type I and II alveolar cells was reported in patients with chronic lung disease. This suggests that overexpression of DPP4 on vascular endothelia and immune cells could attribute to CoV-linked disease [114].

Studies suggested that the S1 domain of SARS-CoV-2 S protein aids as the viral binding site and interrelates with DPP4. The interaction of DPP4 with MERS-CoV S protein triggers signals that hinder the activation of macrophages. Macrophage infection secondary to MERS-CoV S protein pseudotyped particles also defeats the macrophage replies through elevating the synthesis of LPS-induced immunosuppressive cytokine IL-10 and through dropping their capability of synthesizing IL-6 and TNF alpha in naive and LPS-activated THP-1 macrophages. Above all inhibition of DPP4 through sitagliptin/siRNA, a DPP4 inhibitor reduced the activity of the MERS-CoV S protein on IL-1 receptor-associated kinase, peroxisome-proliferator-activated receptors, and IL-10 suggesting that hindering the DPP4 receptors could have a significant role in the modulation of the COVID-19 infection immune response [115].

3.4. Membrane Fusion Blocker (Angiotensin-Converting Enzyme 2) is a Target for COVID-19 Treatment

The first stage of viral infection is the identification of receptors by the S1 subunit of the coronavirus spike protein, followed by receptor-binding domain binding to the receptors. Angiotensin-converting enzyme 2 (ACE2) is used by SARS-CoV-2 and SARS-CoV as a receptor to mediate viral entry into the target cell. The early stages of in vitro SARS-CoV-2 infection can be suppressed by human recombinant soluble ACE2, which has been studied in clinical trials for the management of acute pulmonary injury and pulmonary hypertension, indicating that therapeutic agents acting on the ACE2 pathway may have a beneficial role in the management of COVID-19 infection [116].

In vivo studies have shown that chronic treatment with angiotensin II type 1 receptor antagonists such as olmesartan, losartan, and lisinopril facilitates renal and cardiac angiotensin-converting enzyme 2 receptors gene expression [117]. However, following the entry of severe acute respiratory syndrome virus into respiratory epithelial cells inhibits the effect of angiotensin-converting enzyme 2 receptors thereby increasing the levels of angiotensin II. This leads to severe lung impairment [118]. Though, treatment with angiotensin receptor blocker and angiotensin-converting enzyme inhibitors may be crucial for the survival of a patient infected with COVID-19 through attenuating the cardiac stress and reduce vasoconstriction and profibrotic activity of angiotensin 2 in alveolar capillaries [119].

3.5. Membrane Fusion Blocker (CD147) as a Target for COVID-19 Treatment

In addition to ACE2, CD147 plays a significant role in the pathogenesis of SARS-COV-2 to invade host cells. Therefore, therapeutic agents that affect the interaction of the CD147 expression and spike protein, including progenitor/stem cells, can inhibit the viral dissemination and invasion amongst other cells. The beneficial effect of azithromycin in the management of patients with COVID-19 infection is linked with its effect with interfering with the ligand of CD147. Moreover, besides the potential invasion outcome, treatment with azithromycin reduces the expression of certain metalloproteinases (downstream to CD147) and induces antiviral responses in rhinovirus-infected primary human bronchial epithelial infections, minimizing viral replication and releasing viral infection [120].

4. Nonpharmacologic Treatment and Traditional Herbal Medicines for COVID-19

Recently, debatable thoughts between the COVID-19 infection and immune system are forwarded. Different studies recommended that reducing stress, having regular exercise, eating a balanced diet with fruits and vegetables, avoiding smoking, and getting enough sleep are some of the suggested approaches to trigger the immune system [121].

The use of traditional medicines for the management of the infectious disease has increased because of several reasons including the participation of different concerned bodies in the production and investigations of herbal-based medicines [122, 123]. Recently, several studies were conducted in elucidating the medicinal values of herbal medicines for the management of COVID-19 [124]. Previously, plant-derived herbal medicines have been employed for the management of different outbreaks including H1N1 influenza and SARS [125, 126]. Currently, several countries such as South Korea and China have agreed on guidelines on the use of traditional medicine for the management of COVID-19 [127]. In China, eighty-five percent of COVID-19 infected patients received traditional medicine [124]. A recent study revealed that traditional medicines are supposed to competitively target angiotensin-converting enzyme 2 receptor similar to SARS-CoV- 2 and SARS-CoV. This revealed the possibilities of traditional medicine for the management of SARS-CoV-2 [128]. Plant-based traditional medicines such as Radix platycodonis, Agastache rugosa, Saposhnikoviae divaricata, Lonicerae japonicae flos, Astragalus membranaceus, Rhizoma Atractylodis Macrocephalae, Glycyrrhiza uralensis, Atractylodis Rhizoma, Fructus forsythia, and Cyrtomium fortunei J. Sm were the most commonly used herbal medicine for the management of COVID-19 in China [129].

5. Conclusion

This literature review and analysis were conducted based on newly published studies on the treatment and protection of COVID-19 infection. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. The drug-repurposing trial summarized in the present review mainly concentrated on agents presently identified to be effective against RNA viruses such as influenza, SARS-CoV, Ebola, MERS-CoV, and HCV. The possible impact of biologics for the management of COVID-19 infection is auspicious and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and different types of vaccines. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The evidence summarized in this review provides a strong intellectual groundwork for the development and discovery of vaccines and drugs against COVID-19 infection.

6. Limitations of the Review

Even if this review has its strengths, such as the inclusion of many recent published research works and critically appraising the selected studies, it is not without limitations. The limitations of the current review are the complete reliance on previously published researches.

Abbreviation

2019 nCOV: | 2019 novel coronavirus
ACE-2: | Angiotensin-converting enzyme 2
COV: | Coronavirus
CQ: | Chloroquine
DPP4: | Dipeptidyl-peptidase
HCQ: | Hydroxychloroquine
HIV: | Human immunodeficiency virus
MERS-COV: | Middle east respiratory syndrome coronavirus
NAC: | N-Acetylcysteine
RdRP: | RNA-dependent RNA polymerase
RNA: | Ribonucleic acid
RBD: | Receptor binding domain
TMPRSS2: | Transmembrane protease, serine 2.

Conflicts of Interest

The authors declare that they have no competing interests.

Acknowledgments

The authors would like to acknowledge the University of Gondar for providing materials.

References

S. P. Adhikari, S. Meng, Y.-J. Wu et al., “Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review,” Infectious Diseases of Poverty, vol. 9, no. 1, p. 29, 2020.

WHO, Coronavirus Disease 2019 (COVID-19): Situation Report, WHO, Geneva, Switzerland, 2020.

T. P. Velavan and C. G. Meyer, “The COVID-19 epidemic,” 2020.

CDC. About COVID-19. 2020 [cited 2020 September 30]; Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it.

Hopkins J., Coronavirus Resource Center. Im Internet (Stand: 19.04. 2020): https://coronavirus. jhu. edu/data, 2020.

S. G. V Rosa and W. C. Santos, “Clinical trials on drug repositioning for COVID-19 treatment,” Revista Panamericana de Salud Pública, vol. 44, p. e40, 2020.

S. Monti, P. Delvino, E. Bellis, V. S. Quadrelli, and C. Montecucco, “Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies,” Annals of the Rheumatic Diseases, vol. 79, no. 5, pp. 667-668, 2020.

E. Mahase, “Covid-19: where are we on vaccines and variants?” British Medical Journal, vol. 372, p. n597, 2021.

Food and Drug Administration, Emergency Use Authorization (EUA) of the Pfizer-Biontech COVID-19 Vaccine to Prevent Coronavirus Disease 2019 (COVID-19), Food and Drug Administration, Silver Spring, MS, USA, 2019.

S. E. Oliver, J. W. Gargano, H. Scobie et al., “The advisory committee on immunization practices’ interim recommendation for use of janssen COVID-19 vaccine-United States, February 2021,” MMWR. Morbidity and Mortality Weekly Report, vol. 70, no. 9, pp. 329–332, 2021.

Z. Khan, Y. Karataş, A. F. Ceylan, and H. Rahman, “COVID-19 and therapeutic drugs repurposing in hand: the need for collaborative efforts,” Le Pharmacien Hospitalier et Clinicien, vol. 56, no. 1, pp. 3–11, 2021.

T. L. Doan, M. Pollastri, M. A. Walters, and G. I. Georg, “The future of drug repositioning,” Annual Reports in Medicinal Chemistry, Elsevier, Amsterdam, Netherlands, 2011.

Z. Khan, Y. Karataş, and H. Rahman, “Anti COVID-19 drugs: need for more clinical evidence and global action,” Advances in Therapy, vol. 37, no. 6, pp. 2575–2579, 2020.

W. Zhu, C. Z. Chen, K. Gorshkov, M. Xu, D. C. Lo, and W. Zheng, “RNA-dependent RNA polymerase as a target for COVID-19 drug discovery,” Slas Discovery, vol. 25, no. 10, pp. 1141–1151, 2020.

D. Siegel, H. C. Hui, E. Doerffler et al., “Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo [2, 1-f] [triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of ebola and emerging viruses,” Journal of Medicinal Chemistry, vol. 60, no. 5, pp. 1648–1661, 2017.

S. Mulangu, L. E. Dodd, R. T. Davey et al., “A randomized, controlled trial of Ebola virus disease therapeutics,” New England Journal of Medicine, vol. 381, no. 24, pp. 2293–2303, 2019.

T. P. Sheahan, A. C. Sims, S. R. Leist et al., “Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV,” Nature Communications, vol. 11, no. 1, pp. 1–14, 2020.

T. P. Sheahan, A. C. Sims, R. L. Graham et al., “Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses,” Science Translational Medicine, vol. 9, no. 396, 2017.

C. Scavone, S. Brusco, M. Bertini et al., “Current pharmacological treatments for COVID‐19: what’s next?” British Journal of Pharmacology, vol. 177, no. 21, pp. 4813–4824, 2020.

A. Saxena, “Drug targets for COVID-19 therapeutics: ongoing global efforts,” Journal of Biosciences, vol. 45, no. 1, p. 87, 2020.

S. Merat, “SD1000: high sustained viral response rate in 1361 patients with hepatitis C genotypes 1, 2, 3, and 4 using a low-cost, fixed-dose combination tablet of generic sofosbuvir and daclatasvir: a multicenter, phase III clinical trial,” Clinical Infectious Diseases, vol. 70, no. 10, pp. 2206–2212, 2020.

R. Jácome, J. A. Campillo-Balderas, S. Ponce de León, A. Becerra, and A. Lazcano, “Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic,” Scientific Reports, vol. 10, no. 1, p. 9294, 2020.

B. R. Beck, B. Shin, Y. Choi, S. Park, and K. Kang, “Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model,” Computational and Structural Biotechnology Journal, vol. 18, pp. 784–790, 2020.

S. L. Miller, W. W. Nazaroff, J. L. Jimenez et al., “Transmission of SARS‐CoV‐2 by inhalation of respiratory aerosol in the Skagit Valley Chorale superspreading event,” Indoor Air, vol. 31, no. 2, pp. 314–323, 2021.

L. Mao, H. Jin, M. Wang et al., “Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China,” JAMA Neurology, vol. 77, no. 6, pp. 683–690, 2020.

M. Ellul, L. Benjamin, B. Singh, S. Lant, B. Daniel Michael, and A. Easton, “Neurological associations of COVID-19,” The Lancet Neurology, vol. 19, no. 9, pp. 767–783, 2020.

P. Mesci, A. Macia, A. Saleh et al., “Sofosbuvir protects human brain organoids against SARS-CoV-2,” bioRxiv, 2020.

D.-W. Zhang, H.-L. Yan, X.-S. Xu et al., “The selenium-containing drug ebselen potently disrupts LEDGF/p75-HIV-1 integrase interaction by targeting LEDGF/p75,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 35, no. 1, pp. 906–912, 2020.

S. Mukherjee, W. S. Weiner, C. E. Schroeder et al., “Ebselen inhibits hepatitis C virus NS3 helicase binding to nucleic acid and prevents viral replication,” ACS Chemical Biology, vol. 9, no. 10, pp. 2393–2403, 2014.

E.-B. Haddad, K. McCluskie, M. A. Birrell et al., “Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation,” The Journal of Immunology, vol. 169, no. 2, pp. 974–982, 2002.

Y. Simanjuntak, J.-J. Liang, S.-Y. Chen et al., “Ebselen alleviates testicular pathology in mice with Zika virus infection and prevents its sexual transmission,” PLoS Pathogens, vol. 14, no. 2, Article ID e1006854, 2018.

T. Koyanagi, M. Nakamuta, M. Enjoji et al., “The selenoorganic compound ebselen suppresses liver injury induced by Propionibacterium acnes and lipopolysaccharide in rats,” International Journal of Molecular Medicine, vol. 7, no. 3, pp. 321–327, 2001.

G. Feng, K. I. Zheng, Q.-Q. Yan et al., “COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies,” Journal of Clinical and Translational Hepatology, vol. 8, no. 1, pp. 18–24, 2020.

S. Gladilin, H.-J. Bidmon, A. Divanach et al., “Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia,” Archives of Biochemistry and Biophysics, vol. 380, no. 2, pp. 237–242, 2000.

D. Wichmann, “Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study,” Annals of Internal Medicine, vol. 173, no. 12, p. 1030, 2020.

Z. Jin, X. Du, Y. Xu et al., “Structure of M pro from SARS-CoV-2 and discovery of its inhibitors,” Nature, vol. 582, no. 7811, pp. 289–293, 2020.

H. Sies and M. J. Parnham, “Potential therapeutic use of ebselen for COVID-19 and other respiratory viral infections,” Free Radical Biology and Medicine, vol. 156, pp. 107–112, 2020.

C. V. Haritha, K. Sharun, and B. Jose, “Ebselen, a new candidate therapeutic against SARS-CoV-2,” International Journal of Surgery, vol. 84, pp. 53–56, 2020.

M. Tobaiqy, S. Al-Dahery, A. Mujallad et al., “Therapeutic management of COVID-19 patients: a systematic review,” Infection Prevention in Practice, vol. 2, no. 3, 2020.

L. DongS. Hu and J. Gao, “Discovering drugs to treat coronavirus disease 2019 (COVID-19),” Drug Discoveries & Therapeutics, vol. 14, no. 1, pp. 58–60, 2020.

C. Yang, C. Ke, D. Yue et al., “Effectiveness of arbidol for COVID-19 prevention in health professionals,” Frontiers in Public Health, vol. 8, p. 249, 2020.

P. Xu, J. Huang, F. Zhao et al., “Arbidol/IFN-α2b therapy for patients with corona virus disease 2019: a retrospective multicenter cohort study,” Microbes and Infection, vol. 22, no. 4-5, pp. 200–205, 2020.

J. S. Lee and E.-C. Shin, “The type I interferon response in COVID-19: implications for treatment,” Nature Reviews Immunology, vol. 20, no. 10, pp. 585-586, 2020.

S. S. Unhale, Q. Bilai, and S. Sanap, “A review on corona virus (COVID-19),” International Journal of Pharmaceutical and Life Sciences, vol. 6, no. 4, pp. 109–115, 2020.

A. S. Omrani, M. M. Saad, K. Baig et al., “Ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: a retrospective cohort study,” The Lancet Infectious Diseases, vol. 14, no. 11, pp. 1090–1095, 2014.

Y. Song, W. Peng, D. Tang, and Y. Dai, “Protease inhibitor use in COVID-19,” SN Comprehensive Clinical Medicine, pp. 1–8, 2020.

C. M. Chu, V. C. C. Cheng, I. F. N. Hung et al., “Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings,” Thorax, vol. 59, no. 3, pp. 252–256, 2004.

K. S. Chan, S. T. Lai, C. M. Chu et al., “Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study,” Hong Kong Medical Journal, vol. 9, no. 6, pp. 399–406, 2003.

J. He, L. Hu, X. Huang et al., “Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: insights from structures of protease and inhibitors,” International Journal of Antimicrobial Agents, vol. 56, no. 2, Article ID 106055, 2020.

M. L. Agostini, E. L. Andres, A. C. Sims et al., “Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease,” MBio, vol. 9, no. 2, pp. e00221–e00318, 2018.

B. Cao, Y. Wang, D. Wen et al., “A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19,” New England Journal of Medicine, vol. 382, no. 19, pp. 1787–1799, 2020.

S. Khan, K. Dhama, M. Pathak et al., “Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19,” Annals of Clinical Microbiology and Antimicrobials, vol. 19, no. 1, p. 23, 2020.

K. M. Wagstaff, H. Sivakumaran, S. M. Heaton, D. Harrich, and D. A. Jans, “Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus,” Biochemical Journal, vol. 443, no. 3, pp. 851–856, 2012.

M. Silvestri and G. A. Rossi, “Melatonin: its possible role in the management of viral infections-a brief review,” Italian Journal of Pediatrics, vol. 39, no. 1, p. 61, 2013.

V. Srinivasan, M. Mohamed, and H. Kato, “Melatonin in bacterial and viral infections with focus on sepsis: a review,” Recent Patents on Endocrine, Metabolic & Immune Drug Discovery, vol. 6, no. 1, pp. 30–39, 2012.

J. Wu, W. Li, X. Shi et al., “Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (COVID‐19),” Journal of Internal Medicine, vol. 288, no. 1, pp. 128–138, 2020.

R. J. Reiter, P. Abreu-Gonzalez, P. E. Marik, and A. Dominguez-Rodriguez, “Therapeutic algorithm for use of melatonin in patients with COVID-19,” Frontiers in Medicine, vol. 7, p. 226, 2020.

J. Zhang, X. Ma, F. Yu et al., “Teicoplanin Potently Blocks the Cell Entry of 2019-nCoV,” bioRxiv, 2020.

N. Zhou, T. Pan, J. Zhang et al., “Glycopeptide antibiotics potently inhibit cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV),” Journal of Biological Chemistry, vol. 291, no. 17, pp. 9218–9232, 2016.

P. Colson and D. Raoult, “Fighting viruses with antibiotics: an overlooked path,” International Journal of Antimicrobial Agents, vol. 48, no. 4, pp. 349–352, 2016.

R. N. Rozner, A. Freites-Martinez, J. Shapiro, E. B. Geer, S. Goldfarb, and M. E. Lacouture, “Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies,” Breast Cancer Research and Treatment, vol. 174, no. 1, pp. 15–26, 2019.

H. M. Almohanna, M. Perper, and A. Tosti, “Safety concerns when using novel medications to treat alopecia,” Expert Opinion on Drug Safety, vol. 17, no. 11, pp. 1115–1128, 2018.

G. L. Andriole and R. Kirby, “Safety and tolerability of the dual 5α-reductase inhibitor dutasteride in the treatment of benign Prostatic hyperplasia,” European Urology, vol. 44, no. 1, pp. 82–88, 2003.

E. A. Mostaghel, L. Geng, I. Holcomb et al., “Variability in the androgen response of prostate epithelium to 5 -reductase inhibition: implications for prostate cancer chemoprevention,” Cancer Research, vol. 70, no. 4, pp. 1286–1295, 2010.

Y. Wu, A. Godoy, F. Azzouni, J. H. Wilton, C. Ip, and J. L. Mohler, “Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5α-reductase inhibitors,” The Prostate, vol. 73, no. 13, pp. 1470–1482, 2013.

D. J. Tindall and R. S. Rittmaster, “The rationale for inhibiting 5α-reductase isoenzymes in the prevention and treatment of prostate cancer,” Journal of Urology, vol. 179, no. 4, pp. 1235–1242, 2008.

Z. Ghazizadeh, H. Majd, M. Richter et al., “Androgen regulates SARS-CoV-2 receptor levels and is associated with severe COVID-19 symptoms in men,” bioRxiv, 2020.

A. Goren, C. G. Wambier, S. Herrera et al., “Anti‐androgens may protect against severe COVID‐19 outcomes: results from a prospective cohort study of 77 hospitalized men,” Journal of the European Academy of Dermatology and Venereology, vol. 35, no. 1, pp. e13–e15, 2020.

F. A. Cadegiani, J. McCoy, C. G. Wambier, and A. Goren, “Clinical diagnosis of COVID-19: a prompt, feasible, and sensitive diagnostic tool for COVID-19 based on a 1,757-patient cohort (the androCoV clinical scoring for COVID-19 diagnosis),” medRxiv, 2020.

F. A. Cadegiani, A. Goren, and C. G. Wambier, “Spironolactone may provide protection from SARS-CoV-2: targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS),” Medical Hypotheses, vol. 143, Article ID 110112, 2020.

F. A. Cadegiani, C. G. Wambier, and A. Goren, “Spironolactone: an anti-androgenic and anti-hypertensive drug with strong potential to prevent Covid-19 induced acute respiratory distress syndrome (ARDS),” Frontiers in Medicine, vol. 7, p. 453, 2020.

D. A. Zisman, M. Ischwarz, K. J. Anstrom, Collard, and G. W Hunninghake, “A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis,” New England Journal of Medicine, vol. 363, no. 7, pp. 620–628, 2010.

M. Rogosnitzky, E. Berkowitz, and A. R. Jadad, “Delivering benefits at speed through real-world repurposing of off-Patent drugs: the COVID-19 pandemic as a case in point,” JMIR Public Health and Surveillance, vol. 6, no. 2, Article ID e19199, 2020.

N. S. Ahmed, “Tadalafil: 15 years’ journey in male erectile dysfunction and beyond,” Drug Development Research, vol. 80, no. 6, pp. 683–701, 2019.

N. Mondaini, “Phosphodiesterase type 5 inhibitors and COVID-19: are they useful in disease management?” The World Journal of Men’s Health, vol. 38, no. 3, p. 254, 2020.

P. Chansrichavala, U. Chantharaksri, P. Sritara, and S. C. Chaiyaroj, “Atorvastatin attenuates TLR4-mediated NF-[kappa] B activation in a MyD88-dependent pathway,” Asian Pacific Journal of Allergy and Immunology, vol. 27, no. 1, pp. 49–57, 2009.

P. Kruger, M. Bailey, R. Bellomo et al., “A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis,” American Journal of Respiratory and Critical Care Medicine, vol. 187, no. 7, pp. 743–750, 2013.

Q. Ruan, K. Yang, W. Wang, L. Jiang, and J. Song, “Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China,” Intensive Care Medicine, vol. 46, no. 5, pp. 846–848, 2020.

A. V. Ivachtchenko, Y. A. Ivanenkov, O. D. Mitkin et al., “A novel influenza virus neuraminidase inhibitor AV5027,” Antiviral Research, vol. 100, no. 3, pp. 698–708, 2013.

O. Bedi, V. Dhawan, P. L. Sharma, and P. Kumar, “Pleiotropic effects of statins: new therapeutic targets in drug design,” Naunyn-Schmiedeberg’s Archives of Pharmacology, vol. 389, no. 7, pp. 695–712, 2016.

Q. Zhou and J. Liao, “Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy,” Current Pharmaceutical Design, vol. 15, no. 5, pp. 467–478, 2009.

E. A. Williams, V. Russo, S. Ceraso, D. Gupta, and R. Barrett-Jolley, “Anti-arrhythmic properties of non-antiarrhythmic medications,” Pharmacological Research, vol. 156, Article ID 104762, 2020.

E. Fan, D. Brodie, and A. S. Slutsky, “Acute respiratory distress syndrome,” Jama, vol. 319, no. 7, pp. 698–710, 2018.

Y. Feng, “Efficacy of statin therapy in patients with acute respiratory distress syndrome/acute lung injury: a systematic review and meta-analysis,” European Review for Medical and Pharmacological Sciences, vol. 22, no. 10, pp. 3190–3198, 2018.

D. S. Fedson, S. M. Opal, and O. M. Rordam, “Hiding in plain sight: an approach to treating patients with severe COVID-19 infection,” MBio, vol. 11, no. 2, 2020.

Ž. Reiner, M. Hatamipour, M. Banach et al., “Statins and the COVID-19 main protease: in silico evidence on direct interaction,” Archives of Medical Science, vol. 16, no. 3, pp. 490–496, 2020.

Z. Shi and C. A. Puyo, “N-acetylcysteine to combat COVID-19: an evidence review,” Therapeutics and Clinical Risk Management, vol. 16, pp. 1047–1055, 2020.

J. Geiler, M. Michaelis, P. Naczk et al., “N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus,” Biochemical Pharmacology, vol. 79, no. 3, pp. 413–420, 2010.

W.-Z. Ho and S. D. Douglas, “Glutathione and N-acetylcysteine suppression of human immunodeficiency virus replication in human monocyte/macrophages in vitro,” AIDS Research and Human Retroviruses, vol. 8, no. 7, pp. 1249–1253, 1992.

M. Mata, I. Sarrion, M. Armengot et al., “Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine,” PLoS One, vol. 7, no. 10, Article ID e48037, 2012.

Q. Fu, X. Zheng, Y. Zhou, L. Tang, Z. Chen, and S. Ni, “Re-recognizing bromhexine hydrochloride: pharmaceutical properties and its possible role in treating pediatric COVID-19,” European Journal of Clinical Pharmacology, vol. 77, no. 2, pp. 261–263, 2020.

C. C. Chang, A. C. Cheng, and A. B. Chang, “Over‐the‐counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults,” Cochrane Database of Systematic Reviews, vol. 3, 2014.

M. Depfenhart, D. De Villiers, G. Lemperle, and M. Meyer, “Potential new treatment strategies for COVID-19: is there a role for bromhexine as add-on therapy?” Internal and Emergency Medicine, vol. 15, no. 20, p. 1, 2020.

S. Habtemariam, S. Fazel Nabavi, S. Ghavami, A. Cismaru, I. Berindan-Neagoe, and S. Mohammad Nabavi, “Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the transmembrane serine protease 2,” Pharmacological Research, vol. 157, 2020.

J. M. Lucas, C. Heinlein, T. Kim et al., “The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis,” Cancer Discovery, vol. 4, no. 11, pp. 1310–1325, 2014.

L. Yang, Y. Yuan, and X. Tu, “Determination of bromhexine in plasma by gas chromatography-electron capture detection and pharmacokinetic studies,” Chinese Journal of Chromatography, vol. 18, no. 6, pp. 543–545, 2000.

Y. Yang, S. M.-Z. Zhao, H. Shen, D. Wong, and H.-R. Wang, “Potential mechanistic investigation of Bromhexine for the treatment of COVID-19,” Chinese Pharmaceutical Journal, vol. 55, no. 9, 2020.

J. Cai, X. Wang, J. Zhao et al., “Comparison of clinical and epidemiological characteristics of asymptomatic and symptomatic SARS-CoV-2 infection in children,” Virologica Sinica, vol. 35, no. 6, pp. 803–810, 2020.

E. K. McCreary and J. M. Pogue, “Coronavirus disease 2019 treatment: a review of early and emerging options,” Open Forum Infectious Diseases, vol. 7, no. 4, 2020.

J. Gao, Z. Tian, and X. Yang, “Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies,” BioScience Trends, vol. 14, no. 1, pp. 72-73, 2020.

W. Zhang, Y. Zhao, F. Zhang et al., “The use of anti-inflammatory drugs in the treatment of people with severe corona virus disease 2019 (COVID-19): the perspectives of clinical immunologists from China,” Clinical Immunology, vol. 214, 2020.

C. A. Otuechere, “Repurposing of chloroquine and its derivative, hydroxychloroquine for COVID-19: implications for people living with HIV in Africa,” Preprints, 2020.

A. K. Singh, S. Majumdar, R. Singh, and A. Misra, “Role of corticosteroid in the management of COVID-19: a systemic review and a Clinician’s perspective,” Diabetes & Metabolic Syndrome: Clinical Research & Reviews, vol. 14, no. 5, pp. 971–978, 2020.

M. Durand, S. Sardesai, and C. McEvoy, “Effects of early dexamethasone therapy on pulmonary mechanics and chronic lung disease in very low birth weight infants: a randomized, controlled trial,” Pediatrics, vol. 95, no. 4, pp. 584–590, 1995.

P. Horby, W. S. Lim, J. Emberson et al., “Effect of dexamethasone in hospitalized patients with COVID-19–preliminary report,” New England Journal of Medicine, 2020.

A. Berton, N. Prencipe, R. Giordano, E. Ghigo, and S. Grottoli, “Systemic steroids in patients with COVID-19: pros and contras, an endocrinological point of view,” Journal of Endocrinological Investigation, vol. 44, no. 4, 2020.

T. Rhen and J. A. Cidlowski, “Antiinflammatory action of glucocorticoids - new mechanisms for old drugs,” New England Journal of Medicine, vol. 353, no. 16, pp. 1711–1723, 2005.

Y. Mummed, “Molecular targets for COVID-19 drug development: enlightening nigerians about the pandemic and future treatment,” Biosafety and Health, vol. 2, no. 4, 2020.

J. Whisenant and K. Burgess, “Blocking coronavirus 19 infection via the SARS-CoV-2 spike protein: initial steps,” ACS Medicinal Chemistry Letters, vol. 11, no. 6, pp. 1076–1078, 2020.

A. Hussain, A. Hasan, M. M. Nejadi Babadaei et al., “Targeting SARS-CoV2 spike protein receptor binding domain by therapeutic antibodies,” Biomedicine & Pharmacotherapy, vol. 130, Article ID 110559, 2020.

J. Huang, W. Song, H. Huang, and Q. Sun, “Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: from mechanistic studies to clinical trials for COVID-19,” Journal of Clinical Medicine, vol. 9, no. 4, p. 1131, 2020.

S. Ullrich and C. Nitsche, “The SARS-CoV-2 main protease as drug target,” Bioorganic & Medicinal Chemistry Letters, vol. 30, no. 17, Article ID 127377, 2020.

D. Röhrborn, N. Wronkowitz, and J. Eckel, “DPP4 in diabetes,” Frontiers in Immunology, vol. 6, p. 386, 2015.

D. K. Meyerholz, A. M. Lambertz, and P. B. McCray Jr, “Dipeptidyl peptidase 4 distribution in the human respiratory tract,” The American Journal of Pathology, vol. 186, no. 1, pp. 78–86, 2016.

R. Gelman, A. Bayatra, A. Kessler, A. Schwartz, and Y. Ilan, “Targeting SARS-CoV-2 receptors as a means for reducing infectivity and improving antiviral and immune response: an algorithm-based method for overcoming resistance to antiviral agents,” Emerging Microbes & Infections, vol. 9, pp. 1–21, 2020.

X. Wang, S. Xia, Q. Wang et al., “Broad-spectrum coronavirus fusion inhibitors to combat COVID-19 and other emerging coronavirus diseases,” International Journal of Molecular Sciences, vol. 21, no. 11, p. 3843, 2020.

C. M. Ferrario, J. Jessup, M. C. Chappell et al., “Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2,” Circulation, vol. 111, no. 20, pp. 2605–2610, 2005.

D. Gurwitz, “Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics,” Drug development research, vol. 81, no. 5, pp. 537–540, 2020.

R. Wu, L. Wang, X. Liu et al., “An update on current therapeutic drugs treating COVID-19,” Current Pharmacology Reports, pp. 1–15, 2020.

H. Ulrich and M. M. Pillat, “CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement,” Stem Cell Reviews and Reports, vol. 16, no. 3, pp. 434–440, 2020.

B. Berhe, H. Degefa, G. Adhanom et al., “Global epidemiology, pathogenesis, immune response, diagnosis, treatment, economic and psychological impact, challenges, and future prevention of COVID-19: a scoping review,” medRxiv, 2020.

M. R. García-Risco, L. Mouhid, L. Salas-Pérez et al., “Biological activities of Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) plant extracts,” Plant Foods for Human Nutrition, vol. 72, no. 1, pp. 96–102, 2017.

B. P. Gupta, I. Sharma, N. Kohli, S. Sharma, A. Rathi, and A. K. Sharma, “Preliminary clinical assessment and non- toxicity evaluation of an ayurvedic formulation BGR-34 in NIDDM,” Journal of Traditional and Complementary Medicine, vol. 8, no. 4, pp. 506–514, 2018.

Y. Yang, M. S. Islam, J. Wang, Y. Li, and X. Chen, “Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective,” International Journal of Biological Sciences, vol. 16, no. 10, pp. 1708–1717, 2020.

W. Chen, C. E. Danforn Lim, K.-J. Kang, and J. Liu, “Chinese herbal medicines for the treatment of type A H1N1 influenza: a systematic review of randomized controlled trials,” PloS One, vol. 6, no. 12, Article ID e28093, 2011.

L. Xiaoyan, C. S. Lundborg, D. Banghan et al., “Clinical outcomes of influenza-like illness treated with Chinese herbal medicine: an observational study,” Journal of Traditional Chinese Medicine, vol. 38, no. 1, pp. 107–116, 2018.

L. Ang, H. W. Lee, J. Y. Choi, J. Zhang, and M. S. Lee, “Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines,” Integrative Medicine Research, vol. 9, no. 2, Article ID 100407, 2020.

J. Ding, B. Zhang, P.-J. Wang et al., “Analysis on mechanisms and medication rules of herbal prescriptions for nonalcoholic fatty liver disease based on methods of data mining and biological information,” China Journal of Chinese Materia Medica, vol. 44, no. 8, pp. 1689–1695, 2019.

H. Luo, Q. L. Tang, Y.-X. Shang et al., “Can Chinese medicine be used for prevention of corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs,” Chinese Journal of Integrative Medicine, vol. 26, no. 4, pp. 243–250, 2020.