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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 6  |  Issue : 1  |  Page : 21-32

Recent insights of SARS-CoV-2 potential inhibitors


1 Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, Uttar Pradesh, India
2 Department of Chemistry, GLA University, Mathura, Uttar Pradesh, India

Date of Submission14-Sep-2021
Date of Acceptance26-Nov-2021
Date of Web Publication11-Mar-2022

Correspondence Address:
Abhishek Srivastava
Department of Chemistry, GLA University, Mathura - 281 004, Uttar Pradesh
India
Vinay Kumar Singh
Department of Chemistry, Dr. Shakuntala Misra National Rehabilitation University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_229_21

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  Abstract 


The year of 2019–2021 is emergency that the world is facing due to the spread of 2019-nCoV which has created a very critical condition in human society, known as COVID-19. The complex virus belongs to the family of coronaviridae and genera betacoronavirus and spreads through human interaction. The common symptoms observed in infected are a sudden rise in body temperature within 1st to 9th day of infection, problems around the neck and throat from the start of the infection followed by the spread of infection into the lungs that cause novel coronavirus pneumonia and kidney failure. Many of the receptor proteins of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) and target proteins of the human cells are responsible for endocytosis such as main protease or 3C-like protease, RNA polymerase, and spike protein. These proteins play a vital role in the life cycle of SARS-CoV-2. Many of the computational designed drugs and docking-based drugs are reported as anti-COVID-19. Many of the drugs show strong potent activity against this deadly virus. This study demonstrates the synthetic and computational designed approach, drugs, and compounds for the potential inhibition of the SARS-CoV-2 virus. The review will be helpful in finding a new approach of a drug as an inhibitory receptor of SARS-CoV-2.

Keywords: 3C-like protease protein, angiotensin-converting enzyme 2, coronavirus, nucleocapsid protein, papain-like protease, RNA-dependent RNA polymerase, SARS-CoV main protease


How to cite this article:
Faheem M, Singh VK, Srivastava A. Recent insights of SARS-CoV-2 potential inhibitors. Biomed Biotechnol Res J 2022;6:21-32

How to cite this URL:
Faheem M, Singh VK, Srivastava A. Recent insights of SARS-CoV-2 potential inhibitors. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 May 19];6:21-32. Available from: https://www.bmbtrj.org/text.asp?2022/6/1/21/339370




  Introduction Top


In the year 2019–2021, the whole world is facing an enormous health emergency due to novel coronavirus (2019-nCoV), which is named after severe acute respiratory syndrome coronavirus (SARS-CoV-2) and is commonly known as coronavirus disease COVID-19.[1] COVID-19 starts spreading in 2019 and has now become a major health issue worldwide. According to the WHO report, a novel coronavirus (SARS-CoV-2) cases are infected globally,[2],[3] and the WHO has declared coronavirus disease 2019 (COVID-19) as the sixth public health emergency of international concern on 30 January 2020. The journey of coronavirus has started in 1940 and the first case of this virus was reported in 1960.[4],[5],[6],[7]

In the coronavirus family, two species of virus infections have been reported in humans; first was Middle East Respiratory Syndrome CoV which was transmitted by civet cat to human beings and the second was SARS-CoV, where the infection was spread from camels to human beings. Now, it is SARS-CoV-2, which was supposed to spread out from the seafood market (Huanan Seafood Wholesale Market) to human beings.[8],[9] Infection of SARS-CoV-2 shows common symptoms like a high fever that comes between 1 and 9 days of infection, common cold, cough, and breathing difficulty, at the severe stage, this virus affects the kidney which causes novel coronavirus pneumonia (NCP) and ultimately may cause death.[10],[11] [Table 1] demonstrates the symptomatic difference and treatment strategy of common flu and COVID 19.
Table 1: Difference between common flu and coronavirus disease-2019[12]

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Vellingiri et al. collected detailed mechanism and action of the virus in the human cell on a single roof.[12] In this review, we have collected all the information related to the drugs which have the action against COVID-19. Recent anti-SARS-CoV-2 drugs and their target indications are listed in [Table 2].
Table 2: Recent antisevere acute respiratory syndrome coronavirus-2 drugs and their target indications

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SARS-CoV-2 is a complex structure and is made up of two types of protein-structural protein, which is present over the surface of the virus in the form of spike called spike protein, glycoprotein, etc., and nonstructural protein, like 3-chymotrypsin-like protease, papain-like protease (PLpro), helicase, and RNA-dependent RNA polymerase.[24],[25],[26],[27] These four nonstructural proteins are the key to the life cycle of coronavirus. The highly hydrophobic protein envelops the main structure of this novel virus.[28] The inner structure of SARS-CoV-2 is composed of single-strand RNA and hence belongs to genera betacoronavirus.[24],[29]

Literature review data show that SARS-CoV-2 can remain in an active state on a nonliving surface until 9 days at room temperature. The research revealed that the maximum viral load probability of SARS-CoV-2 is in the saliva of the infected person.[30]


  Similarity between SARS-CoV and SARS-CoV-2 Top


89% whole gene,[31] 82% sequence of PLpro,[32] and 96% sequence of main protease (Mpro)[31] are similar with SARS-CoV. Approximately the whole sequence of receptor angiotensin-converting enzyme 2 (ACE2)[23],[33] and 90% sequence of other enzymes are similar to SARS-CoV.[34]


  Classification and Morphology of Coronavirus Top


According to the International Committee on Taxonomy of Viruses, coronavirus belongs to the Coronaviridae family, and this family is further divided into two subfamilies named Letovirinae and Orthocoronavirinae. The subfamily Orthocoronavirinae have four genera, namely Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus.[35]


  Inhibitor Action Top


Novel coronavirus (SARS-CoV-2) is transmitted from human to human. Some of the literature data shows that many of the receptor proteins of the SARS-CoV-2 and target proteins of the human cells are responsible for endocytosis, such as Mpro or 3C-like protease (3CLpro), RNA polymerase, and spike protein as these proteins play a very vital role in the life cycle of RNA virus. Maximum research came out with the inhibition of ACE2 because angiotensin II (AT2) receptor protein, present on the lungs cell surface is responsible for lung viral infection through binding with ACE2 that results in NCP.[36],[37],[38],[39] In this process, AP2-associated protein kinase 1 (AAK1) plays a key role in regulating and endocytosis.[20] Viral infection by SARS-CoV-2 results in a sudden rise in body temperature that is reported in between 1 and 9 days of the infection, issues around the neck region from the start of infection day, and then this infection may spread into the lungs that cause NCP and ultimately kidney failure. Recent literature shows few action plans against SARS-CoV-2 through inhibiting the activity of ACE2, Mpro or 3CLpro, RNA polymerase, spike protein, etc.[40],[41],[42],[43],[44],[45],[46],[47],[48] In this communication, we have covered recent research literature for COVID-19 and evaluated anti-SARS-CoV-2 drugs in a single roof.


  Disinfection on the Surface by the Biocidal Agent Top


Literature shows that SARS-CoV-2 can remain in an active state on a nonliving surface until 9 days at room temperature.[49] The first aim is to prevent human-to-human surface infection because coronavirus spread by an infected person to a healthy person by entering the host cell through the mucous membrane of the nose, eyes, and mouth.[50],[51] The biocidal agents that are effective in the prevention of the spread of coronaviruses are alcohol, hydrogen peroxide, benzalkonium chloride, and sodium hypochlorite.[52] Kampf et al. reported that human coronavirus could be prevented by using sodium hypochlorite (0.1%) or ethanol (62%–71%).[49] Another report by Kampf (2020) also confirmed that sodium hypochlorite (0.1%), hydrogen peroxide (0.5%), ethanol (60%–71%) are very effective against human coronavirus and can be effectively used in the prevention of the infection against SARS-CoV-2.[53]

Xiong et al. screened out the potency of approved anti-COVID-19 drugs and natural products by establishing molecular mechanics using a CODE method (agile discovery method of drugs or natural products for emerging epidemic) in which they combine the natural product with target gene.[14] [Figure 1] demonstrates the structure of few drugs/compounds that can efficiently combine with target gene of CoV-2. Results with ribavirin exhibit the highest and strongest correlation with the SARS-CoV-2-related gene module, and other natural products such as chloroquine[32] 3,4-benzopyrene, apigenin,[31] fumaric acid, rutin,[33] kaempferol also showed higher correlation score with the SARS-CoV-2 gene and are beneficial in developing an anti-COVID-19 drug.[14]
Figure 1: Structure of drugs/compounds having potential anti-COVID-19 activity

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  Developed Human Angiotensin-Converting Enzyme 2 Inhibitor Top


SARS-CoV-2 belongs to the betacoronavirus genus, enters the human cell, and infects the respiratory tract. The human ACE2 receptor is responsible for entry of coronavirus into the lower respiratory tract epithelial cell of humans.[54],[55] ACE2 is the human gene for COVID-19 infection that is why many researchers focused on the development of a drug for ACE2 inhibition for the SARS-CoV-2 prevention. The structures of drugs/compounds for ACE2 inhibition to prevent SARS-CoV-2 are presented in [Figure 2].
Figure 2: Drugs/compounds for angiotensin-converting enzyme 2 inhibition

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Cui et al. reported various drug as ACE2 inhibitors such as fulvestrant (1), pirinixic acid (2), AG-013608, azathioprine (3), and staurosporine (4). Few natural (plant-based) traditional medicines such as andrographis (family: Acanthaceae), urtica (family: Urticaceae), and sambucus (Family: Adoxaceae) are also found effective against COVID-19. Cui et al. used the normalized gene expression datasets, screened by CMap and JMap software in which they set cut off of 2.0 fold change 2.0 to determine the activity of a drug.[13]

Hoffmann et al. found that transmembrane protease, serine 2 enzyme TMPRSS2 is also responsible for the infection of SARS-CoV-2 as the virus spike protein uses TMPRSS2 for entering into the cell.[56] ACE2 and TMPRSS2 both are not highly specific in the lungs. Literature reveals that the spike protein of SARS-CoV-2 weakly binds with ACE2 whereas SARS-CoV binds strongly with ACE2 receptors.[57]

Cui et al. reported angiotensin II receptor type 2 (AGTR2) as another receptor that also binds with the spike protein complex (S-protein) of SARS-CoV-2. AGTR2 has high specificity in the lungs. The docking results exhibit the strong binding affinity (energy score-15.7 kcal/mol) of AGTR2 with S-protein complex of SARS-CoV-2 in comparison to ACE2 (energy score 6.9 kcal/mol).[58] The author also reported two more genes polymeric immunoglobulin receptor and adhesion G protein-coupled receptor F1, found in high specificity in the lungs, and plays a significant role in the possible entry of SARS-CoV-2 into the human cells.[58]

SARS-CoV-2 has a spike protein, which works as a mediator between receptor and coronavirus for the possible entry of the virus into the human cells.[23] The S-protein of SARS-CoV-2 is subdivided into two units as S1 and S2. The S1 makes a large receptor-binding domain and S2 makes a stalk of the spikes on the virus capsule.[59] To stop the infection of COVID-19, Wei et al. designed some molecules using a machine intelligence-based generative network complex approach containing protease inhibitor that stops the cleavage of S-protein into S1 and S2. They also reported the binding affinity of designed molecules with SARS-CoV-2 [Table 3].[31]
Table 3: 2019-nCoV protease inhibitor with ΔG kcal/mol

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Sarkar et al. published a scientific report on the docking result with some Indian medicinal plant phytochemicals with spike protein fragment with ACE2. In this report, some of the phytochemicals give excellent result and give best docking score as the chloroquine and hydroxychloroquine. The docking score of phytochemicals is hesperidin – 8.99, emodin – 6.19, anthraquinone – 6.15, rhein – 8.73, chrysin – 6.87, chloroquine – 8.98, and hydroxychloroquine – 7.82.[60]


  Main Protease or Chymotrypsin-like Protease Inhibitor Top


3C-like proteinase or coronavirus 3CLpro or coronavirus Mpro is part of a family of enzymes found in SARS-CoV-2.[61] 3CLpro plays a vital role in the replication or duplication of RNA. Mpro enzyme of SARS-CoV-2 is similar to SARS-CoV by about 96%.[17],[31]

Zhavoronkov et al. designed some new compounds by the homology modeling-based generator, ligand-based generator, and crystal-derived pocked-based generator. These compounds are effective in SARS-CoV-2 as PLpro inhibitor and can be effectively used for the prevention of coronavirus.[29]

Hilgenfeld et al. (2020) found that alpha-keto amide derivative [Figure 3] compounds are effective against alpha and beta coronavirus. These compounds exhibit excellent activity against the Mpro of CoV. The compounds show excellent activity against anti-MERS-CoV or anti-SARS-CoV toward infected Huh7 cells.[62] Xu et al. reported docking-based model drug as Mpro inhibitor. The approved drugs such as nelfinavir, perampanel, praziquantel, eszopiclone, zopiclone, and pitavastatin show excellent binding affinity with target molecule. Among these, nelfinavir exhibits excellent binding affinity with Mpro, with binding free energy of 24.69 kcal/mole.[16] Zeng et al. also reported approved drugs as Mpro inhibitors based on the docking with Mpro of SARS-CoV. He used Mpro of SARS-CoV as the target molecule because the Mpro sequence of SARS-CoV shows 96% similarity with SARS-CoV-2. Nelfinavir, prulifloxacin, bictegravir, and tegobuvir show best activity against Mpro.[17] Using computer-based pharmacological study, Kang et al. reported that the ritonavir and lopinavir show the best activity as Mpro inhibitor and could be used as an effective drug against M protease inhibitor.[63]
Figure 3: Drugs/compounds for main protease inhibition

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Kumar et al. screened out natural drugs for the inhibitor of 3CLpro by the computational approach. They used several natural inhibitors as ligand, docked with coronavirus receptor binding site, and found that methyl tanshinonate has the best activity against spike protein.[28] Chen et al. (2020) reported 3CLpro inhibitor agent, screened by the computational approach, and found that ledipasvir[20] and velpatasvir[40] have the potent activity against 3CLpro and will be very effective in viral enzymes as an inhibitor agent [Figure 4].[64]
Figure 4: Drugs/compounds for 3C-like protease inhibition

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Several potential classes of drugs are effective against SARS-CoV-2 Mpro. Among these, indole lactam-based inhibitors, drugs from Indian traditional medicine, phytochemicals, anilid-based inhibitors, peptide-based inhibitors, and α-ketoamide inhibitors are the famous drug classes studied well.[65],[66],[67]


  RNA-dependent RNA Polymerase Inhibitor Top


The atazanavir[42] drug, used for the treatment of antihuman immunodeficiency virus, also shows good inhibitory potency toward SARS-CoV-2 3C-like proteinase (Kd = 94.94). Using the molecule transformer-drug target interaction (MT-DTI) model, Kang et al. reported docking data, which show that atazanavir[42] binds with all replication or duplication component unit such as 2'-O-ribose methyltransferase, RNA-dependent RNA polymerase, endo RNAse, helicase, and 3'-to-5' exonuclease subunit.[63]

Nucleoside-based derivatives (approved drugs) such as ribavirin,[23] remdesivir,[43] and galidesivir[44] have the property against RNA-dependent RNA polymerase that inhibits the activity of enzyme as a result RNA synthesis is blocked. Remdesivir, an adenine derivative compound, is under trial and used 200 mg OD in the 1st day and 100 mg OD for 9 days, giving a good response as anti-COVID-19.[15],[24] Some other compounds [Table 4] are also under trial and can be used against the component of the SARS-CoV-2 complex.[24]
Table 4: Drugs and their inhibition profile

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The chloroquine,[60] remdesivir,[43] and lopinavir[39] exhibit high potent activity against SARS-CoV-2. Chloroquine[60] is widely used for the treatment of malaria and autoimmune disease whereas some of the recent data revealed that chloroquine also has the antiviral property and can be capable to inhibit the glycosylation of cellular receptor of SARS-CoV and reduce the risk of viral infection. The research result shows that the EC90 value of chloroquine for SARS-CoV-2 is 6.90 μ M.[15]

Dang et al. analyzed some approved chemical compounds for COVID-19 on a virtual screen and find that nelfinavir,[32] bictegravir,[37] lopinavir,[39] ritonavir,[41] and sofosbuvir[48] drugs show high binding affinity with target site of SARS-CoV-2 component. They analyzed data by using docking and other deep learning model methods [Table 5].[18]
Table 5: Approved drugs, their inhibitor activity and target indication[46]

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  Papain-like Protease Inhibitor Top


Angiotensin II (AT2) receptor protein, present on the lung cell surface is responsible for lung viral infection.[39] AT2 binds with ACE2 of the SARS-CoV-2 causes NCP. Endocytosis is regulated by AAK1. Stebbing et al. target AAK1 and inhibit its activity by baricitinib.[49] The drug reduces the virus entry in the cell by exhibiting an excellent binding capacity with AAK1.[20] PLpro enzyme plays an important part in the lifecycle of the RNA virus and is helpful for replication.[21] Anti-SARS drugs such as mycophenolic acid,[50] compound 45 and compound 46, and anti-HCV drugs such as grazoprevir,[53] boceprevir,[51] telaprevir[52] show potent activity against SARS-CoV-2. These drugs have the property to inhibit PLpro of SARS-CoV-2 and can be a good candidate as effective drugs for anti-NCP.[21] Lim et al. proposed that a very interesting hypothesis for the inhibiting activity of SARS-CoV-2. Zn plays a very important role in replication and viral infection. Lim et al. used an an-ejecting agent disulfiram,[47] which binds with Cys and forms disulfiram-Cys complex resulted in the loss of protein active site and finally stops the replication of RNA.[19] The structure of PLpro drugs is represented in [Figure 5].
Figure 5: Drugs/compounds for papain-like protease inhibition

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  Inhibition of Nucleocapsid Protein Top


In the coronavirus structure, nucleoprotein is the critical component that plays a vital role in the viral life cycle such as RNA replication or duplication, interferon inhibition, actin reorganization, host cell cycle progression, apoptosis and regulates cell metabolism like gene transcription.[68],[69],[70],[71],[72],[73] N-protein, present inside the virus structure, binds with RNA viral genome to make a complex structured virion core ribonucleoprotein having the long helical structure.[72],[73],[74],[75] Literature revealed that N-protein contains three domains, N-terminal domain (NTD), C-terminal domain (CTD), and linker region (LR). For RNA binding and oligomerization, CTDs play an important role, whereas NTDs are responsible for the RNA binding. LR is the RNA binding region and primary phosphorylation site.[72],[76],[77]

Previous study shows that the N-protein of coronavirus is used as an antiviral drug target against viral infections by blocking RNA synthesis. Hou et al. reported numerous ligands that can effectively join with the NTD of N-protein. Hou et al. developed a new N-protein inhibitor as PJ34[55] which hinders viral infection. The docking study shows that ligand binds with ribonucleotide-bonding pocket.[16] In further study compound, 48 is docked with CoV nucleocapsid protein (NP), the result shows that ligand hits with a ribonucleotide-bonding pocket of CoV NP.[78] In both ligands, polycyclic aromatic core interacts with CoV NP by π-π sacking.[78] Recently, Wagstaff et al. reported that ivermectin, which is used in parasitic infection, also exhibits nuclear transport inhibitory activity.[22] Hou et al. developed a new type of drug based on a small molecule protein–protein interaction stabilizer exhibiting antiviral activity. 5-benzyloxygramin[56] is used as a stabilizer that stabilizes the N-NTD dimers through simultaneous hydrophobic interactions.[76] The strategy of developing a new drug has been useful in the future to develop anti-COVID-19. Many of the research already reported that pyrimidone derivatives have the potential against viral infection.[79],[80] Medhi et al. chose two nitrogen atoms containing dione derivatives from the zinc database and performed docking with N-protein of SARS-CoV. The docking ability of theophylline[57] 3,4-dihydropyrimidone[58] and their derivative were evaluated by the computational method. These molecules have the ability to bind with the RNA binding region and inhibit RNA binding to the NTD of N-protein.[79],[81],[82],[83],[84],[85] Theophylline is also used in therapy for respiratory diseases. [Figure 6] represents the structure of drugs/compounds exhibiting NP inhibition.
Figure 6: Drugs/compounds for nucleocapsid protein inhibition

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  Anti-Novel Coronavirus Pneumonia Drugs Top


Wang et al. reported some natural drugs as anti-NCP on behalf of docking with ACE2 and Mpro.[10] In this research, 38 Chinese patent drugs are reported as ACE2 inhibitors and Mpro inhibitors. Out of which 10 compound screened out by the computational method name as hesperidin[17] (docking score with two receptor Mpro-8.5, ACE-11.4), saikosaponin A[62] (Mpro-8.8, ACE2-11), rutin[61] (Mpro-8.9, ACE2-10.7), corosolic acid[63] (Mpro-8.8, ACE-10.2), verbascoside[64] (Mpro-8.4, ACE-10.6), baicalin[16] (Mpro-8.4, ACE-10.5), glycyrrhizin[65] (Mpro-8.9, ACE-9.9), mulberroside A[66] (Mpro-7.7, ACE-11), cynaroside[67] (Mpro-8.4, ACE2-10.2), and bilirubin[15] (Mpro-7.8, ACE-10.7) give the best docking score and bind with both ACE2 receptor and viral Mpro receptor.[10] Structure of some important anti-NCP drugs/compounds is represented in [Figure 7].
Figure 7: Structure of anti-novel coronavirus pneumonia drugs/compounds

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  Conclusion Top


At present, this virus is growing very fast and is spreading all over the world. Best scientific communities are working together to defeat this deadly virus and take the world toward a better tomorrow. In this review, we represent the computationally based drugs and synthetic approach mostly for the prevention of COVID-19. An infected human to a healthy human with direct contact spreads this virus, and when the virus enters into the host cell it shows, some of the common symptoms like a sudden rise in body temperature and causes NCP. Many of the computational designed drugs and docking-based drugs are reported as anti-COVID-19, and some of the drugs are undergoing trial because these drugs show strong activity against SARS-CoV-2. The components of this virus-like spike protein, helicase, proteinase, or RNA polymerase are a type of protein that is responsible for the replication of genetic material and has a significant position in the life cycle of SARS-CoV-2. Many of the other receptor proteins of the SARS-CoV-2 and target proteins on the human cells are also responsible for endocytosis, such as ACE2, Mpro, or 3CLpro, spike protein are playing a vital role in the life cycle of SARS-CoV-2. Nowadays, many researchers are working to find suitable new drugs for precluding SARS-CoV-2 and are developing new drugs to inhibit the target protein like spike protein, 3CLpro, proteinase, RNA polymerase, NP, and helicase. In this review, we have summarized and listed new and approved drugs. This review will be helpful in finding a new approach drug as an inhibitory receptor of SARS-CoV-2 structure and their life cycle.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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