Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

Developing a safe and effective antiviral treatment takes a decade, however, when it comes to the coronavirus disease (COVID-19), time is a sensitive matter to slow the spread of the pandemic. Screening approved antiviral drugs against COVID-19 would speed the process of finding therapeutic treatment. The current study examines commercially approved drugs to repurpose them against COVID-19 virus main protease using structure-based in-silico screening. The main protease of the coronavirus is essential in the viral replication and is involved in polyprotein cleavage and immune regulation, making it an effective target when developing the treatment. A Number of approved antiviral drugs were tested against COVID-19 virus using molecular docking analysis by calculating the free natural affinity of the binding ligand to the active site pocket and the catalytic residues without forcing the docking of the ligand to active site. COVID-19 virus protease solved structure (PDB ID: 6LU7) is targeted by repurposed drugs. The molecular docking analysis results have shown that the binding of Remdesivir and Mycophenolic acid acyl glucuronide with the protein drug target has optimal binding features supporting that Remdesivir and Mycophenolic acid acyl glucuronide can be used as potential anti-viral treatment against COVID-19 disease.

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“…Extensive studies repurposed antiviral drugs against M pro [ 19 , 46 , 47 ], (Z [ 9 ]. Abd El-Mordy et.…”

Section: Discussionmentioning

confidence: 99%

In silico molecular docking analysis for repurposing approved antiviral drugs against SARS-CoV-2 main protease

Khater

Nassar

2021

Biochemistry and Biophysics Reports

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“…Domain III (residues 198–303) regulates 3CL pro homodimerization, which is required for enzymatic activity [ 14 ]. 3CL pro is widely regarded as an excellent target for COVID-19 drug development because it is essential for viral replication and has a cleavage specificity distinct from human cellular proteases, reducing the likelihood of off-target effects [ 13 , 15 , 16 ]. The preferred sequence at cleavage sites is LQ ↓ (S, A, G), with the arrow indicating the cleavage site [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

Rawson

Duchon

Nikolaitchik

et al. 2021

Viruses

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The 3C-like protease (3CLpro) of SARS-CoV-2 is considered an excellent target for COVID-19 antiviral drug development because it is essential for viral replication and has a cleavage specificity distinct from human proteases. However, drug development for 3CLpro has been hindered by a lack of cell-based reporter assays that can be performed in a BSL-2 setting. Current efforts to identify 3CLpro inhibitors largely rely upon in vitro screening, which fails to account for cell permeability and cytotoxicity of compounds, or assays involving replication-competent virus, which must be performed in a BSL-3 facility. To address these limitations, we have developed a novel cell-based luciferase complementation reporter assay to identify inhibitors of SARS-CoV-2 3CLpro in a BSL-2 setting. The assay is based on a lentiviral vector that co-expresses 3CLpro and two luciferase fragments linked together by a 3CLpro cleavage site. 3CLpro-mediated cleavage results in a loss of complementation and low luciferase activity, whereas inhibition of 3CLpro results in 10-fold higher levels of luciferase activity. The luciferase reporter assay can easily distinguish true 3CLpro inhibition from cytotoxicity, a powerful feature that should reduce false positives during screening. Using the assay, we screened 32 small molecules for activity against SARS-CoV-2 3CLpro, including HIV protease inhibitors, HCV protease inhibitors, and various other compounds that have been reported to inhibit SARS-CoV-2 3CLpro. Of these, only five exhibited significant inhibition of 3CLpro in cells: GC376, boceprevir, Z-FA-FMK, calpain inhibitor XII, and GRL-0496. This assay should greatly facilitate efforts to identify more potent inhibitors of SARS-CoV-2 3CLpro.

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“…One reason for this is the limited number of X-ray structures deposited in the Protein Data Bank (PDB) for PLpro (around 24 structures) compared to the main protease (Mpro, around 200 structures). Additionally, compared to Mpro[ [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] ], fewer reports about targeting PLpro is presented in literature[ [46] , [47] , [48] , [49] , [50] , [51] , [52] ]. In the context of drug repurposing to treat COVID-19, Balasubramaniam et al [ 46 ] reported potential targeting of three SARS-CoV-2 proteins, RNA-dependent RNA polymerase, papain-like proteinase and helicase, by the antiviral drug elbasvir through virtual screening of 54 FDA-approved antivirals and 3300 investigational drugs.…”

Section: Introductionmentioning

confidence: 99%

Targeting multiple conformations of SARS-CoV2 Papain-Like Protease for drug repositioning: An in-silico study

Ismail

Ragab

Bekhit

et al. 2021

Computers in Biology and Medicine

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Papain-Like Protease (PLpro) is a key protein for SARS-CoV-2 viral replication which is the cause of the emerging COVID-19 pandemic. Targeting PLpro can suppress viral replication and provide treatment options for COVID-19. Due to the dynamic nature of its binding site loop, PLpro multiple conformations were generated through a long-range 1 micro-second molecular dynamics (MD) simulation. Clustering the MD trajectory enabled us to extract representative structures for the conformational space generated. Adding to the MD representative structures, X-ray structures were involved in an ensemble docking approach to screen the FDA approved drugs for drug repositioning endeavor. Guided by our recent benchmarking study of SARS-CoV-2 PLpro, FRED docking software was selected for such virtual screening task. The results highlighted potential consensus binders to many of the MD clusters as well as the newly introduced X-ray structure of PLpro complexed with a small molecule. For instance, three drugs Benserazide, Dobutamine and Masoprocol showed a superior consensus enrichment against the PLpro conformations. Further MD simulations for these drugs complexed with PLpro suggested the superior stability and binding of dobutamine and masoprocol inside the binding site compared to Benserazide. Generally, this approach can facilitate identifying drugs for repositioning via targeting multiple conformations of a crucial target for the rapidly emerging COVID-19 pandemic.

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Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19

Cited by 100 publications

References 62 publications

In silico molecular docking analysis for repurposing approved antiviral drugs against SARS-CoV-2 main protease

In silico molecular docking analysis for repurposing approved antiviral drugs against SARS-CoV-2 main protease

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

Targeting multiple conformations of SARS-CoV2 Papain-Like Protease for drug repositioning: An in-silico study

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