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 Table of Contents  
MINI REVIEW
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 17-20

Potential inhibitor for 2019-novel coronaviruses in drug development


1 Department of Chemical Drug, Lanzhou Institutes for Food and Drug Control, Lanzhou, Gansu, China
2 Department of Pharmacy, First Hospital of Lanzhou University, Lanzhou, Gansu, China
3 Department of Biliary-Pancreatic Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
4 Department of Pneumology, First Lanzhou People's Hospital, Lanzhou, Gansu, China
5 Department of Surgery, Gansu People's Hospital, Lanzhou, Gansu, China
6 Department of Medicine, The Fifth People's Hospital of Zhuhai, Zhuhai, Guangdong, China

Date of Submission07-Feb-2020
Date of Acceptance04-Mar-2020
Date of Web Publication25-Mar-2020

Correspondence Address:
Prof. Guoyu Qiu
Department of Chemical Drug, Lanzhou Institutes for Food and Drug Control, No. 988, Peng Jia Ping Town, Lanzhou 730050, Gansu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_3_20

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  Abstract 


The coronavirus disease 2019 (COVID-19), which is first detected in Wuhan, China, is a virus identified as the cause of pneumonia. In the event of epidemic outbreak, a series of actions have been taken by the Chinese government to control the pandemic of the virus, and effective medical methods are in urgent need to prevent COVID-19 infection and cure the disease, especially a drug that can suppress COVID-19 is urgently needed. However, there are no specific drugs and vaccine that can prevent coronavirus infection. Some research works on the transmissibility, severity, and other features associated with this virus are ongoing. Some works about new drug against COVID-19 are carried out; more time is required to develop an effective drug against pneumonia caused by COVID-19. Now, to develop broad-spectrum antiviral agents, there is a quick method to identify drugs with high binding capacity with COVID-19 by virtual screening based on the clinical drug libraries; all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of COVID-19. In this article, we summarize the discovery and clinical application of specific drugs against COVID-19 as potential inhibitors to alleviate the current epidemic.

Keywords: Coronavirus disease-19, coronaviruses, drug candidate, drug development, potential inhibitor


How to cite this article:
Xu X, Dang Z, Zhang L, Zhuang L, Jing W, Ji L, Qiu G. Potential inhibitor for 2019-novel coronaviruses in drug development. Cancer Transl Med 2020;6:17-20

How to cite this URL:
Xu X, Dang Z, Zhang L, Zhuang L, Jing W, Ji L, Qiu G. Potential inhibitor for 2019-novel coronaviruses in drug development. Cancer Transl Med [serial online] 2020 [cited 2020 May 28];6:17-20. Available from: http://www.cancertm.com/text.asp?2020/6/1/17/281363




  Introduction Top


Coronaviruses (CoVs) were recognized as typically causing pneumonia until the emergence of severe acute respiratory syndrome-CoV (SARS-CoV) in 2002 and Middle East respiratory syndrome-CoV (MERS-CoV) in 2012.[1],[2] These CoVs are associated with respiratory syndromes that spread from person to person via close contact, resulting in high morbidity and mortality caused by the progression to acute respiratory distress syndrome. The coronavirus disease 2019 (COVID-19) is a newly emerged human infectious CoV that originated in Wuhan, China.[3] The current outburst of COVID-19 has resulted in regional and global public health emergencies, hence both public health and medicinal measures will be needed to contain the spreading of the virus and to optimize patient outcomes. While research is known about the virus, an examination of the genome sequence shows a strong homology with its more well-studied cousin, SARS-CoV. As far, there is no medical evidence to support the efficacy of the existing antiviral drugs against COVID-19, but the CoVs are positive-sense, single-strand RNA viruses; the COVID-19 genome encodes nonstructural proteins (such as 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase [RdRp]), structural proteins (such as spike glycoprotein), and accessory proteins [Figure 1];[4] and thus share properties with other single-stranded RNA viruses such as hepatitis C virus, West Nile virus, Marburg virus, HIV virus, Ebola virus (EBOV), dengue virus, and rhinoviruses. The potential for the future emergence of CoVs indicates that antiviral drug discovery will require activity against multiple CoVs, so that identifying the drug treatment options as soon as possible is critical for the response to the COVID-19 outbreak. The drug-repurposing approach is an assuring strategy in finding new potential antiviral agents within a short span of time to overcome the challenges in antiviral therapy, which one of those against virus may also inhibit COVID-19. It has been demonstrated that some antiviral activity of inhibitors has inhibiting effect on COVID-19. In the face of this epidemic, it is urgent to further study the CoV and to develop effective drugs and vaccines for COVID-19. In this article, we summarize potential inhibitors for COVID-19 which have been reported in literature for drug development, accomplishing these goals and expectations, to find target compounds to treat the lung infection caused by COVID-19, to study its reliable clinical effect, and to develop a new drug for COVID-19.
Figure 1: Genomic organization of the coronavirus disease 2019[4]

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  Approach to Screen Potential Inhibitor for Coronavirus Disease 2019 Top


The sequence identity between them is as high as 79.5% even though COVID-19 is significantly different from SARS-CoV. Further studies conclusively showed that the similarity of the sequence of the main protease between COVID-19 and SARS-CoV is up to 96.1% based on sequence alignment.[5] It is demonstrated that the main protease of SARS-CoV is essential for viral replication in the life cycle of the virus, which is considered to be an attractive target for drug development.[6] Thus, this protein could be used as a homologous target to screening drugs that inhibit the replication and proliferation of COVID-19; this protein mainly consists of 3C-like protease (3CLpro), papain-like protease (PLpro), and RdRp. 7 Hence, a computational approach to screen for available commercial medicines which may function as inhibitors for the COVID-19 is adopted.[8] Based on the results from bioinformatics analysis, the structure of COVID-19 protein was selected as a homologous target for molecule screening. Then, in silico high-throughput screening strategy and automatic pipeline have been established by using classic docking software and our in-house program, which greatly accelerate the screening process.[9] The overall workflow of virtual screening of small chemical compounds against the COVID-19 main protease is shown in [Figure 2].[10] However, treatment of CoVs in outbreak settings has focused on therapeutics with general antiviral activity and good safety profiles rather than efficacy data provided by cellular, rodent, or nonhuman primate models of highly pathogenic CoV infection.[11]
Figure 2: The overall workflow of virtual screening of chemical compounds against the coronavirus disease 2019 main protease[10]

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  Potential Inhibitor for Coronavirus Disease 2019 Top


Sofosbuvir

Sofosbuvir [Figure 3], a nucleotide analog hepatitis C virus NS5B polymerase inhibitor, is used to treat chronic hepatitis C as a component of a combination antiviral regimen. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of sofosbuvir for the treatment of chronic hepatitis C.[12],[13] The most important druggable targets of Sofosbuvir is the RNA-dependent RNA polymerase(RdRp), which is incorporated into RNA, and due to modifications at the 2' position, inhibits further RNA chain extension and halts RNA replication. In clinical practice, sofosbuvir can inhibit RdRp of the hepatitis C virus, it acts as an RNA polymerase inhibitor by competing with natural ribonucleotides. According to insight that hepatitis C virus and CoV use a similar viral genome replication mechanism, sofosbuvir will also inhibit CoVs, including COVID-19.[14]
Figure 3: Structure of sofosbuvir

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Lopinavir/ritonavir

Lopinavir and ritonavir [Figure 4] are HIV-1 protease inhibitors, which are efficient drugs for HIV infection treatment.[15] A previous attempt to predict drugs for the 3CLpro of SARS-CoV has identified lopinavir and ritonavir, as potential candidates, both of which bind to the same target site of 3CLpro and exhibit some signs of effectiveness against the SARS virus.[16],[17] Based on statistical analysis plan for a recursive, two-stage, group sequential, randomized controlled trial, the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS was found.[17] The combined use of different antiviral agents might be synergistic in the treatment of CoV infection. Based onin vitro andin vivo activities against MERS-CoV, a clinical trial has been designed using a combination of lopinavir-ritonavir and interferon-β1b therapies in hospitalized MERS patients in Saudi Arabia.[18] The Food and Drug Administration has approved lopinavir–ritonavir to inhibit the entry and/or replication of MERS-CoV and SARS-CoV in multiple cell lines.[19] Now, clinical application of these two drugs on COVID-19 patients also appears to be effective, demonstrating the importance of the drug-binding site for suppressing COVID-19 3CLpro activity.[20]
Figure 4: Structures of lopinavir and ritonavir

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Nelfinavir and bictegravir

Nelfinavir [Figure 5] is an anti-HIV drug, which inhibits the cleavage of the polyprotein gag-pol as a protease inhibitor, whereas bictegravir is a new and potent HIV-1 integrase inhibitor, which can efficiently prevent HIV from multiplying and can reduce the amount of HIV in the body. Based on the pockets' functions of target protein, it suggested that nelfinavir and bictegravir should possess the abilities to block the active sites or interrupt the dimer formation of viral protein.[21],[22] Therefore, nelfinavir and bictegravir may serve as promising candidates for drug repurpose and development against COVID-19.
Figure 5: Structures of nelfinavir and bictegravir

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Remdesivir

Remdesivir [Figure 6] is a nucleoside analog. Nucleoside analogs can have multiple mechanisms of action, including lethal mutagenesis, obligate or nonobligate chain termination, and perturbation of natural nucleotide triphosphate pools via inhibition of nucleotide biosynthesis.[23] Remdesivir has demonstrated antiviral activityin vitro against several viral families of emerging infectious diseases including Filoviridae, Pneumoviridae, Paramyxoviridae, and Coronaviridae.[24],[25],[26] Remdesivir, which was developed by Gilead to treat EBOV infections, is a broad-spectrum antiviral nucleotide prodrug with potentin vitro antiviral activity against a diverse panel of RNA viruses such as EBOV, Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus, Nipah virus, and Hendra virus under clinical development. The mechanism of remdesivir's anti-MERS-CoV activity is likely through premature termination of viral RNA transcription.[27],[28] It has been reported that remdesivir inhibited COVID-19 (EC50 =0.77 μM in Vero E6 cells),[29] and the first case of 2019 novel CoV in the United States was treated successfully by taking remdesivir.[30] Two Phase III trials were initiated to evaluate intravenous remdesivir in patients with COVID-19 in early February 2020, with estimated completion dates in April 2020.
Figure 6: Structure of remdesivir

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  Discussion Top


In addition to these above potential inhibitors, there were other promising inhibitors, such as favipiravir,[31] ribavirin, and galidesivir.[17] However, above all, there are no clinically effective drugs for COVID-19 for the moment. Hence, in order to find effective drugs quickly to alleviate the current epidemic, there are two ways by which new drug can be found. One is rapid screening of effective drugs for suppressing COVID-19 according to the current clinical use of broad-spectrum antiviral drugs. The other is to use the drug molecular compound library, combined with the computer drug design, to screen the compounds that may have therapeutic effect on CoV. In this study, we discussed how to screen promising drug candidates for COVID-19 with the help of high-throughput screening technology based on the clinical drug libraries and molecular docking. Meanwhile, we introduce some antiviral drugs that have similar properties with single-stranded RNA of COVID-19 and may serve as promising drug candidates for further study against COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]



 

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