key: cord-0965017-bek4gcff
authors: Luo, Lianxiang; Qiu, Qin; Huang, Fangfang; Liu, Kaifeng; Lan, Yongqi; Li, Xiaoling; Huang, Yuge; Cui, Liao; Luo, Hui
title: Drug repurposing against coronavirus disease 2019 (COVID-19): A review
date: 2021-09-04
journal: J Pharm Anal
DOI: 10.1016/j.jpha.2021.09.001
sha: f87c346ce78a9274f5d16280617abf7d959aeebb
doc_id: 965017
cord_uid: bek4gcff

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to be the culprit in the coronavirus disease (COVID-19), causing a global pandemic. Despite the existence of many vaccine programs, the number of confirmed cases and fatalities due to COVID-19 is still increasing. Furthermore, a number of variants have been reported. Because of the absence of approved anti-coronavirus drugs, the treatment and management of COVID-19 has become a global challenge. Under these circumstances, drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical trials. Here, we summarize the current status of the application of drug repurposing in COVID-19, including drug repurposing based on virtual computer screening, network pharmacology, and bioactivity, which may be beneficial COVID-19 treatment.

The coronavirus disease 2019 (COVID-19) has spread almost globally, with 201 million confirmed cases and over 4.2 million cumulative deaths as of August 6, 2021 [1, 2] . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of this disease, which poses a great crisis to global human health and economic development [3, 4] . Unfortunately, the global epidemic situation of COVID-19 continues to spread, and no approved specific drugs have been developed. Therefore, there is an urgent need to explore effective therapeutic agents.

Traditional drug discovery is a high-input, long-cycle (10-15 years) , and high-risk process, with low success rates [5, 6] . Drug repurposing is an effective way to solve this problem. Drug repurposing is used to explore new applications of approved or investigational drugs outside the scope of the original medical indication, consisting of four steps: compound identification, compound acquisition, development, and Food and Drug Administration (FDA) post-marketing safety monitoring [7, 8] . Compared to traditional drug discovery, drug repurposing has the advantages of shorter research and development time, less development cost, and lower risk, and may reveal novel targets and pathways for approved drugs [9, 10] . For example, sildenafil, originally developed as an antihypertensive drug, has been used to treat erectile dysfunction and pulmonary hypertension [11] . In addition, thalidomide was first developed as a sedative, but was discontinued after it exhibited serious side effects, resulting in severe skeletal congenital disabilities in neonates; however, it was later serendipitously discovered to be effective in treating erythema nodosum leprosum and multiple myeloma [12, 13] .

However, at present, accident-based drug repurposing plays an inferior role. With the continuous advances in bioinformatics and chemoinformatics, drug repurposing has gradually developed into a data-driven innovative drug development strategy. Many approaches have been used for drug repurposing, including molecular dynamics, molecular docking, network pharmacology, and retrospective clinical analysis [9] .

There is often insufficient time to develop drugs against emergent diseases, and in this context drug repurposing can help to identify drugs which can be quickly applied for clinical purposes. In this review, we focus on in silico, network-based, and activitybased drug repurposing approaches, providing some reference information for COVID-19 therapy.

J o u r n a l P r e -p r o o f

SARS-CoV-2 is an enveloped RNA virus, whose source has not been conclusively clarified, but evidence suggests that it may originate from bats or bat droppings [14] [15] [16] . SARS-CoV-2 encodes four major structural proteins: the spike (S) glycoprotein (cleaved into the S1 and S2 subunits by the transmembrane serine protease 2, TMPRSS2), membrane (M) glycoprotein, envelope (E) protein, and nucleocapsid (N) protein (containing the structural component of the helical nucleocapsid) [17] [18] [19] . It encodes several nonstructural proteins, including 3C-like protease (3CL pro ), RNAdependent RNA polymerase (RdRp), and papain-like protease (PL pro ) [20] . 3CL pro is responsible for viral replication and RdRp in coronavirus replication and transcription [12, 21] . PL pro , a multifunctional enzyme with the ability to antagonize host innate immune responses and process viral polyproteins, is essential for coronavirus replication [22, 23] .

Coronaviruses can enter host cells via endosomal and non-endosomal pathways [24] .

When the cell surface is devoid of extracellular proteases, coronaviruses use the endosomal pathway to enter cells. The energetically unfavorable membrane fusion reaction can be overcome with the assistance of pH-dependent endosomal cysteine protease cathepsins, thereby promoting coronavirus entry into host cells [25] . The cysteine protease cathepsin activates the S glycoprotein, allowing the S glycoprotein to recognize the host cell cluster differentiation 147 (CD147) or receptors angiotensinconverting enzyme 2 (ACE2) [26] [27] [28] . When the endosomal pH is reduced, the viral membrane fuses with the endocytic vesicle membrane, releasing viral RNA into the cytosol [29] . Conversely, in the presence of host proteases, such as TMPRSS2, nonendosomal viruses can enter the plasma membrane [25, 30] .

After the virus enters the cell, essential viral polyproteins are translated and hydrolyzed into effector proteins [31, 32] . Nucleocapsids, composed of genomic RNA and N protein, enter the endoplasmic reticulum (ER) and Golgi apparatus, and are further transported to the budding zone through the ER and Golgi apparatus [32, 33] .

The M glycoprotein interacts with the nucleocapsid to form the basic structure of the virus. Moreover, the S and E glycoproteins combine to form viral vesicles that fuse with the cell membrane and are freed by exocytosis [34] . Non-structural proteins, S glycoprotein, TMPRSS2, and ACE2 are important drug targets for anti-COVID-19 therapies (Fig. 1 ).

J o u r n a l P r e -p r o o f James Whyte Black, a British scientist and Nobel Prize winner in Physiological Medicine, pointed out, "the most fruitful basis for new drug discovery is to start with old drugs." [35] . In the current COVID-19 pandemic, the drug repurposing strategy has played a crucial role. Here, we review potential anti-COVID-19 drugs selected by computer technology, networks, and drug activity [36, 37] (Fig. 2 ).

In silico repurposing is a method based on computer technology to accelerate the discovery of new uses of drugs, which can be used to develop virtual screening platforms, predict the binding affinity between protein targets and ligands, and accelerate and promote the process of drug-target recognition, binding, and successful localization [9, 38] . In recent years, there have been many successful cases of drug repurposing using computer technology. Several important drug targets have been identified in previous studies of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), such as S glycoprotein, ACE2, TMPRSS2, 3CL pro , RdRp, and PL pro [30] . The gene and invasion mechanisms of SARS-CoV-2 are similar to those of SARS-CoV [39] . As a matter of fact, in silico repurposing approaches have been increasingly used during the COVID-19 epidemic, especially using 3CL pro as a target to screen drugs. 3CL pro , a cysteine protease with high homology and structural conservation, is critical for viral replication [40] . Recently, various drugs with 3CL pro inhibitory activity have been screened by molecular docking and molecular dynamics simulations. Viomycin was discovered to combine firmly with SARS-CoV-2 3CL pro by deeply embedding itself inside the binding pocket, and showed a higher CDOCKER energy value than ritonavir and lopinavir did [41] . Conivaptan and azelastine maintained proximity to the SARS-CoV-2 3CL pro binding pocket by participating in hydrophobic interactions with active site residues [42] . Oolonghomobisflavan-A showed many hydrogen bonds with the 3CL pro and high molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding energy [43] . In addition, leupeptin hemisulfate, pepstatin A, nelfinavir, birinapant, lypression, and octreotide have received attention as potential inhibitors of 3CL pro , because they show reasonably well molecular mechanics-generalized born surface area (MM-GBSA) score and possessed drug-like properties [44] . On the other hand, other in silico repurposing approaches were also widely used. In a virtual screening based on electronic pharmacophores, binifibrate, bamifylline, ezetimibe and so on were found to be potential inhibitors of 3CL pro [45] . The Ro5 bioactivity model was used to demonstrate the inhibitory capacity of small molecules against protein J o u r n a l P r e -p r o o f targets. In this model, nelfinavir and itacitinib showed the best inhibitory activity and affinity against 3CL pro with favorable pharmacokinetics, and inhibited viral replication and excessive inflammation [46] . On the basis of virtual screening of ChEMBL database, the results showed that the 28 bioactive compounds targeting SARS-CoV-2 3CL pro , such as sepimostat and curcumin, had considerable affinity for SARS-CoV-2 3CL pro [47] . Moreover, by molecular modeling and virtual screening of SARS-CoV-2 3CL pro , ledipasvir and velpatasvir could relieve fatigue and headache in COVID-19 patients, with minimal side effects [48] , and the combination of ribavirin, telbivudine, vitamin B12, and nicotinamide has been made available as a treatment for COVID-19 [49] .

Besides 3CL pro , other targets have also been studied extensively. Many approved antiviral drugs, such as sofosbuvir, favipiravir, cefuroxime, hydroxychloroquine, and IDX-184, have shown significant binding interactions with RdRp in molecular docking experiments [50] [51] [52] [53] [54] . In addition, casopitant, an inhibitor for the treatment of chemotherapy-induced nausea neurokinin-1 receptor, was shown to inhibit RdRp by virtual screening [55] . By molecular modeling and molecular docking of SARS-CoV-2 PL pro , some anti-viral, anti-bacterial, muscle relaxant, and anti-tussive drugs, such as valganciclovir, thymidine, cefamandole, ecycline, chlorphenesin carbamate, and levodropropizine have been selected to inhibit PL pro [56] . In addition, virtual screening and molecular docking of S glycoprotein showed that ivermectin could be successfully used to control SARS-CoV-2 replication in vitro [57] . 7173 clinically approved drugs were screened with ACE2 as a target, and the results showed that lividomycin, burixafor, quisinostat, fluylline, pemetrexed, proffylline, edotecarin, and diniylline had inhibitory effects on ACE2 [58] . Lucas et al. [59] screened more than 70,000 compounds using a chemical library and concluded that bromhexine hydrochloride had a stimulating inhibitory effect on TMPRSS2. In addition, benzquercin, a TMPRSS2 inhibitor, has been found to affect cellular entry of SARS-CoV-2 [60] .

In summary, the application of in silico repurposing approaches in COVID-19 therapy is mainly related to key protein targets (Table 1) [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] . The rapid development of in silico repurposing approaches provides new methods for new drug research, and is continuously applied in drug repurposing research. At present, in silico repurposing approaches have made a significant contribution in the COVID-19 pandemic.

Nevertheless, further in vivo and in vitro clinical trials are needed to verify this hypothesis.

J o u r n a l P r e -p r o o f Network pharmacology refers to the science of integrating, comparing, and analyzing drug action and biological networks, and exploring the interactions between drugs and specific nodes or modules in the integrated network, to more deeply understand the laws of interaction between medications and the body [61, 62] . With the progress of network biology research, network pharmacology technology provides a new means for drug research and development, which has become an important technology in drug repurposing research. At present, network-based drug repurposing for COVID-19 has been carried out to discover drugs that can effectively treat COVID-19.

Based on the design principle of network-based vitro study, melatonin and toremifene had synergistic effects in reducing viral infection and replication and abnormal inflammatory response, and showed strong biological feasibility [63] . Zhou et al. [64] systematically predicted over 2,000 FDA-approved or experimental drugs based on systems pharmacology and network methods. They also screened 16 drug candidates (e.g., mercaptopurine) and 3 potential drug combinations (e.g., sirolimus plus dactinomycin) for SARS-CoV-2 and these results had some guiding value for preclinical studies and drug combination discovery of old drugs. Protocol for COVID-19 and ephedra-glycyrrhiza drug pair were found to have positive effects on COVID-19, which is worthy of further promotion and application [69, 70] . In summary, in the absence of a specific drug for COVID-19 treatment, network-based drug repurposing is a feasible strategy for discovering effective therapeutics for COVID-19.

Activity-based drug repurposing can be understood as repurposing based on similarities in drug actions (biological effects). For example, some drugs with therapeutic effects on fever, diarrhea, and cough, could be studied to determine whether they may have therapeutic effects on these symptoms in COVID-19 by experimental and clinical trials.

In this outbreak, many active compounds of TCM and TCM herbal formulas have been discovered to have potential activity against COVID-19 [71] . The Lianhuaqingwen capsule (LH) is a finished product of a Chinese herbal formula that exerts broadspectrum antiviral and immunomodulatory effects against various influenza viruses [72] . LH has been approved by the National Health Council for COVID-19 treatment, with the impact of inhibiting the release of inflammatory factors, anti-SARS-CoV-2 replication, and reducing the transcriptional expression of proinflammatory factors [73] .

A clinical trial of 284 patients showed that LH could be considered to improve the clinical symptoms of COVID-19 [74] . Fritillaria, a herbal medicine with multiple active components such as alkaloids and terpenoids, which have anti-inflammatory, anti-cholinesterase, and antiviral activities and anti-tussive, expectorant, anti-asthmatic effects, has been widely applied to treat respiratory diseases, including COVID-19 [75] .

In addition, Luo et al. [76] found that Qingfei Paidu decoction (QFPDD), used to treat non-infectious bronchitis, can aid recovery from COVID-19 and is beneficial for regulating intestinal function and maintaining the balance of the microenvironment.

Many types of Western medicines have also been suggested to be effective. Various drugs with antiviral activity are widely used for treating COVID-19. Lopinavirritonavir, a drug for the treatment of HIV, may act against COVID-19 by inhibiting the coronavirus endopeptidase C30 [77] . Remdesivir is a broad-spectrum antiviral drug with high selectivity for viral polymerases and low toxicity in humans. It binds to RdRp J o u r n a l P r e -p r o o f in the form of nucleoside triphosphates, thereby counteracting the Ebola virus [78] . And remdesivir prevents coronavirus replication by interfering with the viral polymerase activity [79] . The results of preliminary clinical trials showed that patients treated with remdesivir had a 31% faster recovery time than those who received a placebo [80] . Arbidol is a powerful broad-spectrum antiviral drug, whose unique mechanism involves targeting the S glycoprotein/ACE2 interaction, thus inhibiting the fusion of the virus envelope and host cell membrane [81, 82] . Ivermectin, an antiparasitic drug with antiviral effects in vitro, is related to the suppression of the host importin (IMP) α/β1, thereby disrupting the immune escape mechanism [83] . Single increasing the pH of endosomes and lysosomes [92] [93] [94] . Clinical trials have shown that chloroquine effectively treats COVID-19, including improving pulmonary symptoms and shortening the course of disease [92, 95] . However, chloroquine has many side effects, such as diarrhea, rashes, weakness, headaches, and muscle pain, and only showed an inhibitory effect against SARS-COV-2 in vitro at a maximal dose, which could cause serious toxicity [96] . Hydroxychloroquine is also a research hotspot.

Hydroxychloroquine inhibited SARS-CoV-2 more effectively than chloroquine in vitro study [97] , while Tufan et al. [98] pointed out that hydroxychloroquine may be considered as a treatment option for patients with severe COVID-19. Moreover, the time to SARS-CoV-2 clearance can be shortened by the combination of hydroxychloroquine and streptomycin [97] . However, a multicenter, blinded, placebocontrolled randomized trial proved that hydroxychloroquine had no therapeutic benefit in adults hospitalized with COVID-19 [99] .

Severe COVID-19 is characterized by a hyperinflammatory state or even a cytokine storm, resulting in the elevation of a large number of cytokines, such as interleukin 1 and 6 (IL-1 and IL-6) [100, 101] . Therefore, some receptor blockers have received much attention. Anakinra is an anti-interleukin-1 receptor blocker approved for the treatment of rheumatoid arthritis (RA), which has been shown to improve respiratory function and may be beneficial for severe COVID-19 [102, 103] . Tocilizumab, a humanized anti-IL-6 monoclonal antibody, inhibits membrane-bound and soluble IL-6 receptors, which is commonly used in rheumatology [78] . At present, tocilizumab has been successfully applied to a few severe cases of COVID-19 without adverse events [81, 104] . Sarilumab, another IL-6 receptor antagonist, is also available as a treatment for severe COVID-19 [81] . Convalescent plasma (CP) therapy refers to the therapeutic process involving the collection of plasma components from patients recovered from specific infections, and infusing them to critically ill patients to provide passive immunization; this method applied in multiple viral outbreaks including SARS, MERS, Spanish flu, and Ebola [105, 106] . A controlled trial including ten severe patients with severe COVID-19

confirmed that CP could significantly improve oxyhemoglobin saturation, increase lymphocyte counts, and decrease C-reactive protein [107] . Furthermore, CP could promote virus-negative transformation at 72 hours and improve adverse events, but did not result in clinical improvement within 28 days, as reported in an open-label, multicenter, randomized clinical trial [108] .

We can thus conclude that activity-based drug repurposing is an effective and feasible strategy. In this epidemic, various types of drugs were screened and verified by in vivo and in vitro preclinical research, and clinical trials, resulting in the identification of many valuable drugs for COVID-19 treatment.

COVID-19 has been the most widespread global pandemic in the past hundred years.

Drug research and development in response to this sudden outbreak of a pathogenic virus is a major problem that needs to be addressed, and drug repurposing has provided valuable information in this regard.

Here, we summarize several commonly used techniques for drug repurposing and 

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